Substituted 2-carbonylamino-6-piperidinaminopyridines and substituted 1-carbonylamino-3-piperidinaminobenzenes as 5-HT1F agonists

ABSTRACT

The present invention relates to compounds of formula I:  
                 
 
or a pharmaceutically acceptable acid addition salt thereof, wherein X is C(R 3c )═ or N═; R 1  is C 2 -C 6  alkyl, substituted C 2 -C 6  alkyl, C 3 -C 7  cycloalkyl, substituted C 3 -C 7  cycloalkyl, phenyl, substituted phenyl, heterocycle, or substituted heterocycle; R 2  is hydrogen, C 1 -C 3  n-alkyl, C 3 -C 6  cycloalkyl-C 1 -C 3  alkyl, or a group of formula II  
                 
 
provided that when R 1  is C 2 -C 6  alkyl or substituted C 2 -C 6  alkyl, R 2  is hydrogen or methyl; R 3a , R 3b  and, when X is —C(R 3c )═, R 3c , are each independently hydrogen, fluoro, or methyl, provided that no more than one of R 3a , R 3b , and R 3c  may be other than hydrogen; R 4  is hydrogen or C 1 -C 3  alkyl; R 5  is hydrogen, C 1 -C 3  alkyl, or C 3 -C 6  cycloalkylcarbonyl, provided that when R 3a  is other than hydrogen, R 5  is hydrogen; R 6  is hydrogen or C 1 -C 6  alkyl; and n is an integer from 1 to 6 inclusively. The compounds of the present invention are useful for activating 5HT 1F  receptors, inhibiting neuronal protein extravasation, and for the treatment or prevention of migraine in a mammal.

RELATED APPLICATIONS

This application is a continuation of, and claims priority to, priorapplication U.S. Ser. No. 10/569,109, filed Feb. 21, 2006, which claimsthe benefit of PCT/2004/025607, filed Sep. 3, 2004, which claims thebenefit of U.S. Ser. No. 60/502,780, filed Sep. 12, 2003, now abandoned.The contents of these applications are incorporated by reference hereinin their entireties.

BACKGROUND OF THE INVENTION

Until recently, theories regarding the pathophysiology of migraine havebeen dominated since 1938 by the work of Graham and Wolff. Arch. Neurol.Psychiatry, 39: 737-63, 1938. They proposed that the cause of migraineheadache was vasodilatation of extracranial vessels. This view wassupported by knowledge that ergot alkaloids and sumatriptan, ahydrophilic 5-HT₁ agonist which does not cross the blood-brain barrier,induce contraction of cephalic vascular smooth muscle and are effectivein the treatment of migraine. Humphrey, et al., Ann. NY Acad. Sci., 600:587-600, 1990. Recent work by Moskowitz has shown, however, that theoccurrence of migraine headaches is independent of changes in vesseldiameter. Cephalalgia, 12: 5-7, 1992.

Moskowitz has proposed that currently unknown triggers for painstimulate trigeminal ganglia that innervate vasculature within thecephalic tissue, giving rise to release of vasoactive neuropeptides fromaxons on the vasculature. These released neuropeptides then activate aseries of events, a consequence of which is pain. This neurogenicinflammation is blocked by sumatriptan and ergot alkaloids by mechanismsinvolving 5-HT receptors, believed to be closely related to the5-HT_(1D) subtype, located on the trigeminovascular fibers. Neurology,43 (suppl. 3): S16-S20 1993. Sumatriptan, in fact, has high affinity forthe 5-HT_(1B) and 5-HT_(1D) receptors, K_(i)=10.3 nM and 5.1 nM,respectively, which activity may be indicative of vasoconstrictiveactivity. Sumatriptan and similar compounds previously advanced for thetreatment of migraine had tended to be selected on the basis of thisvasoconstrictive activity under the premises of the prior art models formigraine.

Serotonin (5-HT) exhibits diverse physiological activity mediated by atleast seven receptor classes, the most heterogeneous of which appears tobe 5-HT₁. A human gene which expresses one of these 5-HT₁ receptorsubtypes, named 5-HT_(1F), was isolated by Kao and coworkers. Proc.Natl. Acad. Sci. USA, 90: 408-412, 1993. This 5-HT_(1F) receptorexhibits a pharmacological profile distinct from any serotonergicreceptor yet described. It was found that sumatriptan, in addition tothe above mentioned strong affinities for the 5-HT_(1B) and 5-HT_(1D)receptors, also has affinity for the 5-HT_(1F) receptor subtype, with aK_(i) of about 23 nM. This suggests a possible role for the 5-HT_(1F)receptor in migraine.

Various 5-HT_(1F) receptor agonists have subsequently been developedwhich have shown relative selectivity for the 5-HT_(1F) receptorsubclass and it has been shown that such selectivity generally reducesthe vasoconstrictive activity characteristic of other compounds advancedas potential agents for the treatment of migraine and associateddisorders.

Included among these 5-HT_(1F) receptor agonists are compounds disclosedin the following:

-   -   U.S. Pat. Nos. 5,708,187 and 5,814,653, describing a family of        6-substituted-3-amino (alkyl)-tetrahydrocarbazoles and        7-substituted-4-amino(alkyl)cyclohepta[7,6b]Indoles;    -   U.S. Pat. No. 5,521,196, U.S. Pat. No. 5,721,252, U.S. Pat. No.        5,521,197, and WO 96/29075, describing various families of        5-substituted piperidin-3-yl-indoles and 5-substituted 1,2,3,6        tetrahydropyridin-3-yl-indoles;    -   WO 97/13512 describing a family of 5-substituted        3-aminoethylindoles;    -   WO 98/46570 describing a family of 5-substituted indoles,        pyrrolo[3,2-b]pyridines, benzofurans, and benzothiophenes,        having the 3-position substituted with octahydroindolizinyl,        octahydro-2H-quinolizinyl, decahydropyrido[1,2-a]azepinyl, 1,        2,3,5,8,8a-hexahydroindolizinyl,        1,3,4,6,9,9a-hexahydro-2H-quinolizinyl, or        1,4,6,7,8,9,10,10a-octahydropyrido[1,2-a]azepinyl;    -   WO 98/20875 and WO 99/25348 describing two families of        5-substituted piperidin-3-yl-azaindoles and 5-substituted        1,2,3,6-tetrahydropyridin-3-yl-azaindoles;    -   WO 00/00487 describing a family of 5-substituted (piperidin-3-yl        or 1,2,3,6-tetrahydropyridin-3-yl)indoles, azaindoles,        benzofurans, and benzothiophenes;    -   WO 98/08502 describing a family of        8-substituted-1,2,3,4-tetrahydro-2-dibenzofuranamines and        9-substituted-2-aminocyclohepta[b]benzofurans;    -   WO 98/55115 describing a family of        3-amino-1,2,3,4-tetrahydro-9H-carbazole-6-carboxamides and        4-amino-10H-cyclohepta[7,6-b]indole-7-carboxamides;    -   WO 98/15545 describing a select family of 3,5-disubstituted        indoles and benzofurans;    -   WO 00/00490 describing a family of 5-allyl-substituted        (piperidin-3-yl or 1,2,3,6-tetrahydropyridin-3-yl)indoles,        azaindoles, benzofurans, and benzothiophenes;    -   WO 00/47559 describing a family of        4-(3-substituted-benzoyl)piperidines;    -   WO 00/50426 describing a family of 3,5-disubstituted        azabenzofurans; and    -   WO 00/34266 describing a family of 3-heteroaryl-5-(2-(aryl or        heteroaryl)-2-oxoethyl) indoles.

Continued research has now surprisingly yielded a new and unexpectedclass of novel selective 5-HT_(1F) agonists having distinct chemical andreceptor binding properties, which inhibit peptide extravasation, whileavoiding significant vasoconstrictive activity, and are therefore usefulfor the treatment of migraine and other 5-HT_(1F) receptor associateddisorders.

SUMMARY OF THE INVENTION

The present invention relates to substituted2-carbonylamino-6-piperidinaminopyridines and substituted1-carbonylamino-3-piperidinaminobenzenes compounds of the generalformula I:

or a pharmaceutically acceptable acid addition salt thereof, where;

X is —C(R^(3c))═ or —N═;

R¹ is C₂-C₆ alkyl, substituted C₂-C₆ alkyl, C₃-C₇ cycloalkyl,substituted C₃-C₇ cycloalkyl, phenyl, substituted phenyl, heterocycle,or substituted heterocycle;

R² is hydrogen, C₁-C₃ n-alkyl, C₃-C₆ cycloalkyl-C₁-C₃ alkyl, or a groupof formula II

provided that when R¹ is C₂-C₆ alkyl or substituted C₂-C₆ alkyl, R² ishydrogen or methyl;

R^(3a), R^(3b) and, when X is —C(R^(3c))═, R^(3C), are eachindependently hydrogen, fluoro, or methyl, provided that no more thanone of R^(3a), R^(3b), and R^(3c) may be other than hydrogen;

R⁴ is hydrogen or C₁-C₃ alkyl;

R⁵ is hydrogen, C₁-C₃ alkyl, or C₃-C₆ cycloalkylcarbonyl, provided thatwhen R^(3a) is other than hydrogen, R⁵ is hydrogen;

R⁶ is hydrogen or C₁-C₆ alkyl; and

n is an integer from 1 to 6 inclusively.

The present invention also relates to pharmaceutical compositionscomprising a compound of formula I, or a pharmaceutically acceptableacid addition salt thereof, and a pharmaceutically acceptable carrier,diluent, or excipient. In another embodiment, the present inventionrelates to pharmaceutical compositions adapted for the activation of5-HT_(1F) receptors, for the inhibition of neuronal proteinextravasation, and/or for the treatment or prevention of migraine inmammals, particularly humans, containing a compound of formula I, or apharmaceutically acceptable acid addition salt thereof, and apharmaceutically acceptable carrier, diluent, or excipient.

In addition, the present invention relates to a method for activating5-HT_(1F) receptors in mammals, particularly humans, comprisingadministering to a mammal in need of such activation an effective amountof a compound of formula I, or a pharmaceutically acceptable acidaddition salt thereof.

Moreover, the present invention relates to a method for inhibitingneuronal protein extravasation in mammals, particularly humans,comprising administering to a mammal in need of such inhibition aneffective amount of a compound of formula I, or a pharmaceuticallyacceptable acid addition salt thereof.

Additionally, the present invention relates to a method for treating orpreventing migraine in mammals, particularly humans, comprisingadministering to a mammal in need of such treatment or prevention, aneffective amount of a compound of formula I, or a pharmaceuticallyacceptable acid addition salt thereof.

Another aspect of the present invention relates to the use of a compoundof formula I as a medicament, and in particular a medicament adapted forthe activation of 5-HT_(1F) receptors, for the inhibition of neuronalprotein extravasation, and/or for the treatment or prevention ofmigraine in mammals, particularly humans. That is to say, the presentinvention relates to the use of a compound of formula I for theactivation of 5-HT_(1F) receptors, for the inhibition of neuronalprotein extravasation, and/or for the treatment or prevention ofmigraine in mammals, particularly in humans.

Additionally, the present invention relates to the use of one or morecompounds of formula I in the manufacture of a medicament for theactivation of 5-HT_(1F) receptors, for the inhibition of neuronalprotein extravasation, and/or for the treatment or prevention ofmigraine in mammals, particularly in humans.

Furthermore, the present invention provides for methods for thetreatment and/or prevention of 5-HT_(1F)-mediated disorders comprisingadministering to a mammal in need of such treatment or prevention,particularly a human, an effective amount of a compound of formula I, ora pharmaceutically acceptable acid addition salt thereof. In preferredembodiments, the 5-HT_(1F)-mediated disorder is neuronal proteinextravasation and/or migraine.

DETAILED DESCRIPTION OF THE INVENTION

The following detailed description is provided to aid those skilled inthe art in practicing the present invention. Even so, the followingdescription should not be construed to unduly limit the presentinvention in that modifications and variations in the embodimentsdiscussed herein can be made by those of ordinary skill in the artwithout departing from the spirit or scope of the present inventivediscovery. Such modifications and variations are contemplated as beingwithin the scope of the invention.

One embodiment of the present invention is a method for increasingactivation of 5-HT_(1F) receptors, while avoiding vasoconstrictiveactivity, for treating a variety of disorders that have been linked todecreased neurotransmission of serotonin in mammals. Included amongthese disorders are migraine, general pain, trigeminal neuralgia, dentalpain or temperomandibular joint dysfunction pain, anxiety, generalanxiety disorder, panic disorder, depression, disorders of sleep,chronic fatigue syndrome, premenstrual syndrome or late luteal phasesyndrome, post-traumatic syndrome, memory loss, dementia includingdementia of aging, social phobia, autism, attention deficithyperactivity disorder, disruptive behavior disorders, impulse controldisorders, borderline personality disorder, obsessive compulsivedisorder, premature ejaculation, erectile dysfunction, bulimia, anorexianervosa, alcoholism, tobacco abuse, mutism, and trichotillomania. Thecompounds of this invention are also useful as a prophylactic treatmentfor migraine. Any of these methods employ a compound of formula I. Inpreferred embodiments, the mammal to be treated by the administration ofthe compounds of formula I is human.

In those instances where the disorders which can be treated by serotoninagonists are known by established and accepted classifications, theirclassifications can be found in various sources. For example, atpresent, the fourth edition of the Diagnostic and Statistical Manual ofMental Disorders (DSM-IV™) (1994, American Psychiatric Association,Washington, D.C.), provides a diagnostic tool for identifying many ofthe disorders described herein. Also, the International Classificationof Diseases, Tenth Revision (ICD-10), provides classifications for manyof the disorders described herein. The skilled artisan will recognizethat there are alternative nomenclatures, nosologies, and classificationsystems for disorders described herein, including those as described inthe DSM-IV and ICD-10, and that terminology and classification systemsevolve with medical scientific progress.

The use of a compound of formula I for the activation of the 5-HT_(1F)receptor, for the inhibition of neuronal peptide extravasation, ingeneral or due to stimulation of the trigeminal ganglia specifically,and/or for the treatment of any of the disorders described above, areall embodiments of the present invention. In one preferred embodiment,the invention provides a method for the treatment of migraine in amammal, as for example a human, comprising administering to a mammal inneed of such treatment, a pharmaceutically effective amount of acompound of formula I. In another preferred embodiment, the inventionprovides a method for the prevention of migraine in a mammal, as forexample a human, comprising administering to a mammal in need of suchtreatment, a pharmaceutically effective amount of a compound of formulaI.

Likewise, the use of a compound of formula I, or a combination of morethan one compound of formula I, in the manufacture of a medicament forthe activation of the 5-HT_(1F) receptor, for the inhibition of neuronalpeptide extravasation, in general or due to stimulation of thetrigeminal ganglia specifically, and/or for the treatment of any of thedisorders described above, are also all embodiments of the presentinvention.

The general chemical terms used throughout have their usual meanings.For example, the term alkyl refers to a branched or unbranched saturatedhydrocarbon group. The term “n-alkyl” refers to an unbranched alkylgroup. By way of illustration, but without limitation, the term “C₁-C₂alkyl” refers to methyl and ethyl. The term “C₁-C₃ n-alkyl” refers tomethyl, ethyl, and n-propyl. The term “C₁-C₃ alkyl” refers to methyl,ethyl, n-propyl, and isopropyl. The term “C₁-C₄ alkyl” refers to methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl.The term “C₁-C₆ alkyl” refers to all branched and unbranched alkylgroups having from one to six carbon atoms. The term “C₂-C₆ alkyl”refers to all branched and unbranched alkyl groups having from two tosix carbon atoms. The term “C₃-C₆ cycloalkyl” refers to cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl. The term “C₃-C₇ cycloalkyl”also includes cycloheptyl. Cycloalkylalkyl refers to a cycloalkyl moietylinked through an n-alkyl chain, as for example, but not limited to,“C₃-C₆ cycloalkyl-C₁-C₃ alkyl,” which refers to a C₃-C₆ cycloalkylmoiety linked through a 1 to 3 carbon n-alkyl chain. Each alkyl,cycloalkyl, and cycloalkylalkyl group may be optionally substituted asprovided for herein. Among compounds wherein R¹ is cycloalkyl, compoundswherein X is —N═ are preferred over compounds wherein X is —C(R^(3C))═.

The terms “alkoxy”, “phenyloxy”, “benzyloxy” and “pyrimidinyloxy” referto an alkyl group, phenyl group, benzyl group, or pyrimidinyl group,respectively, each optionally substituted as provided for herein, thatis bonded through an oxygen atom.

The terms “alkylthio”, “phenylthio”, and “benzylthio” refer to an alkylgroup, phenyl group, or benzyl group, respectively, each optionallysubstituted as provided for herein, that is bonded through a sulfuratom.

The term “C₁-C₄ acyl” refers to a formyl group or a C₁-C₃ alkyl groupbonded through a carbonyl moiety. The term “C₁-C₄ alkoxycarbonyl” refersto a C₁-C₄ alkoxy group bonded through a carbonyl moiety. The term C₃-C₆cycloalkylcarbonyl refers to a C₃-C₆ cycloalkyl group bonded through acarbonyl moiety.

The term “halo” refers to fluoro, chloro, bromo, or iodo. Preferred halogroups are fluoro, chloro, and bromo. More preferred halo groups arefluoro and chloro.

The term “heterocycle” is taken to mean a saturated or unsaturated 5- or6-membered ring containing from 1 to 3 heteroatoms selected fromnitrogen, oxygen and sulfur, said ring optionally being benzofused.Exemplary heterocycles, for the purposes of the present invention,include furanyl, thiophenyl, pyrrolyl, pyrrolidinyl, pyridinyl,N-methylpyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl,triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, thiazolidinyl,N-acetylthiazolidinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and thelike. Exemplary benzofused heterocycles, for the purposes of the presentinvention, include isoquinolinyl, benzoxazolyl, benzodioxolyl,benzothiazolyl, quinolinyl, benzofuranyl, benzothiophenyl, indolyl, andthe like, all of which may be optionally substituted, which alsoincludes optionally substituted on the benzo ring when the heterocycleis benzofused.

In one embodiment, preferred heterocycles include furanyl, thiophenyl,pyrrolyl, pyridinyl, N-methylpyrrolyl, pyrimidinyl, pyrazinyl, indolyl,benzofuranyl, benzothiophenyl, benzodioxolyl, and thiazolidinyl, all ofwhich may be optionally substituted.

In yet another embodiment, preferred heterocycles include pyridinyl,thiophenyl, and furanyl, all of which may be optionally substituted.

Substituted alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, or alkylthio,means an alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, or alkylthio group,respectively, substituted one or more times independently with asubstituent selected from the group consisting of halo, hydroxy, andC₁-C₃ alkoxy. Substitutions on cycloalkylalkyl moieties may be on thering portion or the alkyl linker portion or both. Preferredsubstitutions include substitution 1-5 times with halo, eachindependently selected, or substituted 1-3 times with halo and 1-2 timesindependently with a group selected from hydroxy and C₁-C₃ alkoxy, orsubstituted 1-3 times independently with a group selected from hydroxyand C₁-C₃ alkoxy, provided that no more than one hydroxy and/or alkoxysubstituent may be attached through the same carbon.

The terms “substituted phenyl” and “substituted heterocycle” are takento mean that the cyclic moiety in either case is substituted with one ormore halo substituents, preferably one to five, more preferably one tothree, each independently selected; or substituted with one or moresubstituents, preferably one to two substituents, independently selectedfrom the group consisting of halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄alkylthio, cyano, and nitro, wherein each alkyl, alkoxy and alkylthiosubstituent can be further substituted independently with C₁-C₂ alkoxyor with one to five halo groups selected from fluoro and chloro; orsubstituted with one substituent selected from the group consisting ofphenyloxy, benzyloxy, phenylthio, benzylthio, and pyrimidinyloxy,wherein the phenyloxy, benzyloxy, phenylthio, benzylthio, andpyrimidinyloxy moiety can be further substituted with one to twosubstituents selected from the group consisting of halo, C₁-C₂ alkyl,and C₁-C₂ alkoxy, wherein each alkyl and alkoxy group can be furthersubstituted with 1 to 3 fluoro groups; or substituted with onesubstituent selected from the group consisting of C₁-C₄ acyl and C₁-C₄alkoxycarbonyl, and further substituted with zero to one substituentselected from the group consisting of halo, C₁-C₄ alkyl, C₁-C₄ alkoxy,and C₁-C₄ alkylthio. When a substituent is halo, preferred halo groupsare fluoro, chloro, and bromo.

In another embodiment, preferred substitutions for “substituted phenyl”and “substituted heterocycle” include substitution with one or more halosubstituents, preferably one to five, more preferably one to three, eachindependently selected; or substituted with one or more substituents,preferably one to two substituents, independently selected from thegroup consisting of halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, cyano, and nitro,wherein each alkyl and alkoxy substituent can be further substitutedindependently with one to five halo groups selected from fluoro andchloro.

In another embodiment, preferred substitutions for “substituted phenyl”include substitution with one or three independently selected halosubstituents; or substituted with one to two substituents, independentlyselected from the group consisting of halo, methyl, methoxy,trifluoromethyl, trifluoromethoxy, and cyano.

Abbreviations used herein are defined as follows:

BINAP means 2,2′-bis(diphenylphosphino)-1,1′binaphthyl.

DMF means N,N-dimethylformamide.

DMSO means dimethylsulfoxide.

Pd₂(dba)₃ means tris(dibenzylideneacetone)dipalladium(0)

Pd(OAc)₂ means palladium diacetate.

THF means tetrahydrofuran.

The term “amino protecting group” as used in this specification refersto a substituent commonly employed to block or protect the aminofunctionality while reacting other functional groups on the compound.Examples of such amino-protecting groups include the formyl group, thetrityl group, the phthalimido group, the acetyl group, thetrichloroacetyl group, the chloroacetyl, bromoacetyl, and iodoacetylgroups, urethane-type blocking groups such as benzyloxycarbonyl,9-fluorenylmethoxycarbonyl (“FMOC”), t-butoxycarbonyl (t-BOC), and thelike; and like amino protecting groups. The species of amino protectinggroup employed is not critical so long as the derivatized amino group isstable to the conditions of subsequent reactions on other positions ofthe molecule and can be removed at the appropriate point withoutdisrupting the remainder of the molecule. The selection and use(addition and subsequent removal) of amino protecting groups is wellknown within the ordinary skill of the art. Further examples of groupsreferred to by the above terms are described by T. W. Greene and P. G.M. Wuts, “Protective Groups in Organic Synthesis”, 3^(rd) edition, JohnWiley and Sons, New York, N.Y., 1999, chapter 7, hereafter referred toas “Greene”.

The term “pharmaceutical” or “pharmaceutically acceptable” when usedherein as an adjective, means substantially non-toxic and substantiallynon-deleterious to the recipient.

By “pharmaceutical composition” it is further meant that the carrier,solvent, excipients and salt must be compatible with the activeingredient of the composition (e.g. a compound of formula I). It isunderstood by those of ordinary skill in this art that the terms“pharmaceutical formulation” and “pharmaceutical composition” aregenerally interchangeable, and they are so used for the purposes of thisapplication.

The term “acid addition salt” refers to a salt of a compound prepared byreaction of the compound with a mineral or organic acid. The compoundsof the present invention form pharmaceutically acceptable acid additionsalts with a wide variety of organic and inorganic acids and include thephysiologically acceptable salts which are often used in pharmaceuticalchemistry. Such salts are also embodiments of this invention. A“pharmaceutically-acceptable (acid) addition salt” is formed from apharmaceutically-acceptable acid as is well known in the art. Such saltsinclude the pharmaceutically acceptable salts exemplified in Berge, S.M, Bighley, L. D., and Monkhouse, D. C., J. Pharm. Sci., 66:1, (1977),which are well known to those skilled in the art.

Inorganic acids commonly employed to form such salts includehydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,phosphoric acid, and the like. Organic acids commonly employed to formsuch salts include p-toluenesulfonic acid, methanesulfonic acid, oxalicacid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citricacid, benzoic acid, acetic acid and the like. Examples of suchpharmaceutically acceptable salts thus are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, β-hydroxybutyrate, glycollate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, mandelate and the like. It is well known thatsuch compounds can form salts in various molar ratios to provide forexample the hemi-acid, mono-acid, di-acid salts, etc.

The term “effective amount” means an amount of a compound of formula Iwhich is capable of activating 5-HT_(1F) receptors and/or inhibitingneuronal protein extravasation.

The term “suitable solvent” refers to any solvent, or mixture ofsolvents, inert to the ongoing reaction that sufficiently solubilizesthe reactants to afford a medium within which to effect the desiredreaction.

It is understood that compounds of the present invention may exist asstereoisomers. As such, all enantiomers, diastereomers, and mixturesthereof, are included within the scope of the present invention. Wherespecific stereochemistries are identified in this application, theCahn-Prelog-Ingold designations of (R)- and (S)- and the cis and transdesignation of relative stereochemistry are used to refer to specificisomers and relative stereochemistry. While all enantiomers,diastereomers, and mixtures thereof, are contemplated within the presentinvention, preferred embodiments are single enantiomers and singlediastereomers.

While all of the compounds of the present invention are useful as5-HT_(1F) agonists, certain classes are preferred, as for example,compounds having any of the following enumerated selections ofsubstituents: Compounds wherein

-   -   1) R¹ is phenyl, substituted phenyl, heterocycle, or substituted        heterocycle;    -   2) R¹ is substituted phenyl;    -   3) R¹ is mono- or di-substituted phenyl wherein the substituents        are independently selected from halo, C₁-C₄ alkyl, C₁-C₄ alkoxy,        trifluoromethyl, trifluoromethoxy, trifluoroethoxy, phenyloxy,        benzyloxy, cyano, and nitro;    -   4) R¹ is mono- or di-substituted phenyl wherein the substituents        are independently selected from halo, C₁-C₂ alkoxy,        trifluoromethyl, trifluoromethoxy, and trifluoroethoxy;    -   5) R¹ is mono- or di-substituted phenyl wherein the substituents        are independently selected from halo, trifluoromethyl, and        trifluoromethoxy;    -   6) R¹ is mono-, di- or tri-halo substituted phenyl;    -   7) R¹ is heterocycle or substituted heterocycle;    -   8) R¹ is heterocycle or substituted heterocycle wherein the        heterocycle is selected from the group consisting of furanyl,        thiophenyl, pyrrolyl, pyrrolidinyl, pyridinyl, N-methylpyrrolyl,        oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl,        oxadiazolyl, thiadiazolyl, thiazolyl, thiazolidinyl,        N-acetylthiazolidinyl, pyrimidinyl, pyrazinyl, pyridazinyl,        isoquinolinyl, benzoxazolyl, benzodioxolyl, benzothiazolyl,        quinolinyl, benzofuranyl, benzothiophenyl, and indolyl;    -   9) R¹ is a substituted or unsubstituted heterocycle wherein the        heterocycle is selected from the group consisting of pyridinyl,        indolyl, furanyl, benzofuranyl, thiophenyl, benzodioxolyl, and        thiazolidinyl;    -   10) R¹ is a substituted or unsubstituted heterocycle wherein the        heterocycle is selected from the group consisting of pyridinyl,        thiophenyl, and furanyl;    -   11) R¹ is mono-, di-, or tri-halo-substituted heterocycle, each        halo group being independently selected;    -   12) R¹ is mono- or di-substituted heterocycle, wherein one of        the substituents is selected from the group consisting of C₁-C₂        alkoxy, phenoxy, and phenylthio;    -   13) R¹ is mono-substituted heterocycle, wherein the substituents        is halo or nitro;    -   14) R¹ is mono-halo substituted heterocycle;    -   15) R¹ is unsubstituted heterocycle;    -   16) R¹ is C₂-C₆ alkyl;    -   17) R¹ is C₂-C₆ alkyl substituted one to five times with halo;    -   18) R¹ is C₃-C₇ cycloalkyl;    -   19) R¹ is C₃-C₇ cycloalkyl and X is —N═;    -   20) R¹ is cyclopropyl;    -   21) R² is hydrogen or C₁-C₃ n-alkyl;    -   22) R² is hydrogen or methyl;    -   23) R² is pyrazolylalkyl or N-substituted pyrazolylalkyl;    -   24) R² is pyrazol-4-yl-ethyl;    -   25) R² is 1-(C₁-C₃ alkyl)pyrazol-4-yl-ethyl;    -   26) R² is cyclopropylmethyl;    -   27) R^(3a), R^(3b), and R^(3c) if present, are each hydrogen;    -   28) One of R^(3b) or R^(3c) if present, is fluoro;    -   29) R⁴ is hydrogen;    -   30) When X is —C(R^(3C))═, R⁴ is methyl;    -   31) R⁵ is hydrogen;    -   32) R⁵ is methyl;    -   33) R^(3a), R^(3b), and R^(3c) if present, are hydrogen or        fluoro, provided no more than one of R^(3a), R^(3b), and R^(3c)        may be other than hydrogen;    -   34) R^(3a), R^(3b), and R^(3c) if present, are hydrogen or        fluoro, provided no more than one of R^(3a), R^(3b), and R^(3c)        may be other than hydrogen, and R⁴ is hydrogen;    -   35) R^(3a), R^(3b) and R^(3c) if present, are hydrogen or        fluoro, provided no more than one of R^(3a), R^(3b), and R^(3c)        may be other than hydrogen, R⁴ is hydrogen, and R⁵ is hydrogen        or methyl;    -   36) R^(3b), and R^(3c) if present, are hydrogen or fluoro,        provided no more than one of R^(3b) and R^(3c) may be other than        hydrogen, R⁴ is hydrogen, and R⁵ is hydrogen or methyl;    -   37) R² is hydrogen or methyl, R^(3a), R^(3b), and R^(3c) if        present, are each hydrogen or fluoro, provided no more than one        of R^(3a), R^(3b), and R^(3c) may be other than hydrogen, R⁴ is        hydrogen, and R⁵ is hydrogen or methyl;    -   38) R¹ is mono-, di-, or tri-substituted phenyl wherein the        substituents are independently selected from halo, C₁-C₂ alkoxy,        trifluoromethyl, trifluoromethoxy, and trifluoroethoxy, R² is        hydrogen or methyl, R^(3a), R^(3b), and R^(3c) if present, are        each hydrogen or fluoro, provided no more than one of R^(3a),        R^(3b), and R^(3c) may be other than hydrogen, R⁴ is hydrogen,        and R⁵ is hydrogen or methyl;    -   39) R¹ is mono-, di-, or tri-substituted phenyl wherein the        substituents are independently selected from halo, R² is        hydrogen or methyl, R^(3a), R^(3b), and R^(3c) if present, are        each hydrogen or fluoro, provided no more than one of R^(3a),        R^(3b), and R^(3c) may be other than hydrogen, R⁴ is hydrogen,        and R⁵ is hydrogen or methyl;    -   40) R¹ is a substituted or unsubstituted heterocycle selected        from the group consisting of pyridinyl, indolyl, benzofuranyl,        furanyl, thiophenyl, benzodioxolyl, and thiazolidinyl, R² is        hydrogen or methyl, R^(3a), R^(3b), and R^(3c) if present, are        each hydrogen or fluoro, provided no more than one of R^(3a),        R^(3b), and R^(3c) may be other than hydrogen, R⁴ is hydrogen,        and R⁵ is hydrogen or methyl;    -   41) R¹ is a substituted or unsubstituted heterocycle selected        from the group consisting of pyridinyl, thiophenyl, and furanyl,        R² is hydrogen or methyl, R^(3a), R^(3b), and R^(3c) if present,        are each hydrogen or fluoro, provided no more than one of        R^(3a), R^(3b), and R^(3c) may be other than hydrogen, R⁴ is        hydrogen, and R⁵ is hydrogen or methyl;

It will be understood that the above classes may be combined to formadditional preferred classes, as for example the combination ofpreferred selections for two or more substituents. Illustrative examplesof combinations of preferred classes forming additional preferredclasses are:

-   -   42) the combination of any one of preferred classes 1)        through 20) with any one of preferred classes 21) through 26);    -   43) the combination of any one of preferred class 42) with        preferred class 27) or 28);    -   44) the combination of any one of preferred classes 42) or 43)        with preferred class 29) or 30);    -   45) the combination of any one of preferred classes 42), 43),        or 44) with preferred class 31) or 32);

The compounds of the present invention may be synthesized through anumber of alternative routes. Schemes 1-7 relate to the synthesis ofcompounds wherein X is —C(R^(3c))═. Schemes 8 and 9 relate to thesynthesis of compounds wherein X is —N═. Suitable reaction conditionsfor the steps of these schemes are well known in the art and appropriatesubstitutions of solvents and co-reagents are within the skill of theart. Likewise, it will be appreciated by those skilled in the art thatsynthetic intermediates may by isolated and/or purified by various wellknown techniques as needed or desired, and that frequently, it will bepossible to use various intermediates directly in subsequent syntheticsteps with little or no purification. All substituents, unless otherwiseindicated, are as previously defined, and all reagents are well knownand appreciated in the art.

Scheme 1:

Compounds of the present invention wherein X is —CH═ can be synthesizedby methods according to Scheme 1, above, wherein R⁷ is C₁-C₃ n-alkyl,C₃-C₆ cycloalkyl-C₁-C₃ alkyl, or a group of formula II, above, or asuitable nitrogen protecting group. The scheme comprises a reductiveamination of an optionally R³-substituted 3-aminonitrobenzene with theappropriate piperidin-4-one reagent, followed by reduction of the nitrogroup, and finally acylation of the primary amine with the appropriateR¹-acylchloride. Optionally, another reductive amination can then bedone to obtain compounds wherein R⁵ is other than hydrogen. Where R⁷ isa protecting group, removal of the protecting group provides compoundsof the present invention wherein R² is hydrogen. Further compoundswherein R² is other than hydrogen can then be made in a straight forwardmanner by alkylation of the piperidinyl nitrogen.

Reductive amination of 3-aminonitrobenzene with the appropriatepiperidin-4-one reagent can be done in an inert solvent likedichloromethane, THF, toluene, or the like, at temperatures typicallybetween about 0-40° C. in the presence of a borohydride such as sodiumborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, orthe like. Preferably, the reaction is performed in dichloromethane atambient temperature in the presence of sodium triacetoxyborohydride.Reduction of the nitro function by catalytic hydrogenation in thepresence of Pd/C is performed in an appropriate solvent, such asmethanol, ethanol, isopropanol, or the like, at temperatures typicallybetween about 20-40° C. Preferably, the hydrogenation is performed inmethanol at ambient temperature. Finally, the acylation of the primaryamine is run with an excess of the acid chloride, typically betweenabout 1.1-1.3 equivalents, in the presence of an organic base, such astriethylamine, Hunig's base, or the like, in an appropriate solvent suchas THF, CH₂Cl₂, diethyl ether, diisopropyl ether, methyl tert-butylether, dioxane, DMF, toluene, ethylacetate, acetone, or the like, attemperatures typically between about 0-40° C. Preferably, the acylationis performed in THF, acetone or ethyl acetate with 1.1 equivalent of theacid chloride at ambient temperature in presence of 2.2 equivalents oftriethylamine.

Compounds wherein R⁵ is C₁-C₃ alkyl can by made by reductive aminationwith the appropriate aldehyde, in the presence of an organic acid and asuitable borohydride. Preferably, this second amination is performed inmethanol, with acetic acid and sodium cyanoborohydride at ambienttemperature. Compounds wherein R⁵ is C₃-C₆ cycloalkylcarbonyl can bymade by reaction with the appropriate cycloalkylcarbonyl chloridereagent under similar acylation conditions as described above.

Scheme 2:

Alternatively, compounds of the present invention wherein X is —CH═ canbe synthesized by methods according to Scheme 2, above, wherein thecondensation of the optionally R³-substituted 3-aminonitrobenzene withthe appropriate R¹-acylchloride is conducted first, followed byreduction of the nitro group and reductive amination with theappropriate piperidin-4-one reagent. As with Scheme 1, compounds whereinR⁵ is other than hydrogen may be obtained through another reductiveamination at the linker nitrogen. Also as with Scheme 1, where —R⁷ is aprotecting group, removal of the protecting group provides compounds ofthe present invention wherein R² is hydrogen. Further compounds whereinR² is other than hydrogen can then be made in a straightforward mannerby alkylation of the piperidinyl nitrogen.

Typically, combine the optionally R³-substituted 3-aminonitrobenzenewith an appropriate solvent, such as dioxane, pyridine, THF,N,N-dimethylacetamide, or the like. Treat the mixture with theappropriate acid chloride (1.0 to 2.0 equivalents). Stir the reactionfor between about 2-48 hr. at between about 0-40° C., say roomtemperature for about 16 hr. Transfer the reaction mixture into ethylacetate or other suitable solvent, and wash successively with aqueousHCL (1N), aqueous NaOH (1N), saturated aqueous NaCl. Normal workupprocedures on the organic layer provide the benzamide intermediate.

Add the benzamide intermediate to a warm solution (about 35-70° C., sayabout 55° C.) of SnCl₂.2H₂O in ethanol. Add concentrated HCl and thenstir and heat the mixture at between about 50-65° C., say about 60° C.,for between about 20-60 min., say about 30 min. Cool the reactionmixture and then basify the mixture to about pH 14 with aqueous NaOH.Extract the product with an appropriate solvent, such as ethyl acetateor the like. Normal workup procedures on the combined organic layersprovide the aminobenzamide intermediate.

Stir a mixture of the aminobenzamide intermediate,N-protected-4-piperidone, and powdered molecular sieve (4A), in anappropriate solvent such as THF, dichloroethane, methylene chloride, orthe like, under an inert atmosphere. Add glacial acetic acid. Afterbetween about 1-8 hr., say about 1 hr., add NaBH(OC(O)CH₃)₃. Allow themixture to react for about 8-24 hr., at about 0° C.-40° C., say aboutroom temperature. Pour the reaction mixture into a suitable solvent suchas methylene chloride, ethyl acetate, or the like, and wash with aqueousNaOH. Normal workup procedures on the organic layer provide the desiredpiperidinylbenzamide.

As with Scheme 1, the linker nitrogen can optionally be substituted ifdesired to provide compounds wherein R⁵ is other than hydrogen.

Scheme 3:

Compounds of the present invention wherein X is —CH═ may also besynthesized by methods according to Scheme 3, above, comprisingprotection of one amino group of 1,3 diaminobenzene, reductive aminationwith an appropriate piperidin-4-one reagent, deprotection, and finallyacylation of the primary amine with an appropriate R¹-acylchloride.Reaction conditions are similar to those in Schemes 1 and 2, above. Notealso that substitution of the linker nitrogen may be performed before orafter the acylation step, as desired.

Scheme 4:

Compounds of the present invention wherein R^(3c) is fluoro can besynthesized as shown in Scheme 4. An initial reductive amination of3-amino-1-chloro-2-fluorobenzene with an appropriately substituted4-piperidone is followed by conversion of the chloro group to an aminogroup, and subsequent condensation with the appropriate R¹-acylhalidecompound. Reaction conditions are similar to those in Schemes 1-3,above. Note also that substitution of the linker nitrogen may beperformed before or after the acylation step, as desired.

Scheme 5:

Compounds wherein R^(3c) is fluoro and R⁵ is C₁-C₃ alkyl can besynthesized as shown in Scheme 5 showing R⁵=methyl as an example. Aninitial condensation of 1-bromo-2-fluorobenzene with an appropriatelysubstituted 4-aminopiperidine is followed by halogenation of the benzylring, conversion of the halo group to an amino group, and subsequentcondensation with the appropriate R¹-acylhalide compound.

Scheme 6:

Compounds of the present invention wherein R^(3b) is fluoro and R⁵ isC₁-C₃ alkyl can be synthesized as shown in Scheme 6 showing R⁵=methyl asan example. An initial condensation of 1,3-dibromo-5-fluorobenzene withan appropriately substituted 4-aminopiperidine is followed by conversionof the remaining bromo group to an amino group, and subsequentcondensation with the appropriate R¹-acylhalide compound. Alternatively,1,3-difluoro-5-nitrobenzene can be used in the initial condensation withan appropriately substituted 4-aminopiperidine, followed by reduction ofthe nitro group to an amino group, and subsequent condensation with theappropriate R¹-acylhalide compound.

Typically the 1,3-dibromo-5-fluorobenzene dissolved in an appropriatesolvent, such as toluene, benzene, or the like, is combined withmethyl-(1-methylpiperidin-4-yl)amine, sodium t-butoxide, Pd₂dba₃, andBINAP, and heated, as for example, between 50° C. and 100° C., say about80° C., for between about 1-3 hr., say about 2 hr. The reaction isquenched, as for example by addition of water or other suitable means.The (3-bromo-5-fluorophenyl)-methyl-(1-methylpiperidin-4-yl)-amineintermediate may be worked up by common procedures, as for example,solvent removal, extraction procedures, and/or further purification bychromatography, etc.

The (3-bromo-5-fluorophenyl)-methyl-(1-methylpiperidin-4-yl)-amineintermediate is then aminated at the benzo 3-position, as for example,by reacting the intermediate with BINAP, Pd₂dba₃, benzhydrylideneamine,and sodium t-butoxide, in a suitable solvent, such as toluene or thelike, under an inert atmosphere for about 1-3 hr., say about 2 hr., atabout 50° C. to 100° C., say about 80° C. The resulting intermediate istreated with 1M HCl or the like in a suitable solvent, such as THF at 0°C. to ambient temperature, preferably ambient temperature for 1-2 hours,say about 1 hr. The resulting intermediate,5-fluoro-N-methyl-N-(1-methylpiperidin-4-yl)benzene-1,3-diamine may thenbe isolated and purified by common procedures such as, but not limitedto, solvent removal, extraction and/or chromatography, etc.

Final compounds can then be synthesized by condensation with theR¹-acylchloride. Typically, the 5-fluoroaminobenzene intermediate isreacted with the appropriate R¹-acylchloride, in an appropriate solvent,such as dioxane, pyridine, DMF, or the like, at between ambienttemperature and about 100° C., preferably between about 50-100° C.,until the reaction is complete, as for example between about 1-4 hr.,say about 2 hr. The reaction is then quenched by addition of water andthe final product purified by normal work-up procedures.

Alternatively, the5-fluoro-N-methyl-N-(1-methylpiperidin-4-yl)benzene-1,3-diamineintermediate may be prepared by reacting the 1,3-difluoro-5-nitrobenzene with methyl-(1-methylpiperidin-4-yl)amine in the presence ofsodium acetate in a suitable solvent, such as ethanol or the like, forbetween about 8-16 hr., say about 12 hr., at 80-120° C., say about 100°C. in a sealed tube. The reaction is then quenched by the addition ofwater or the like and the(3-fluoro-5-nitrophenyl)-methyl-(1-methylpiperidin-4-yl)amineintermediate is purified by normal work-up procedures. The nitro groupis then reduced to an amino group, as for example, by treatment withiron and 1M HCl in a suitable solvent, such as methanol or the like, forbetween about 8 hr. to overnight, say about 16 hours, at between about80-100° C., say about 100° C. The5-fluoro-N-methyl-N-(1-methylpiperidin-4-yl)benzene-1,3-diamineintermediate may then be isolated and purified by common procedures.

Scheme 7:

Compounds of the present invention wherein R^(3b) is fluoro and R⁵ ishydrogen can be synthesized as shown in Scheme 7, where1,3-dibromo-5-fluorobenzene is converted to a 1,3-diamino compound,condensed with the appropriate R¹-acylhalide compound, followed byreductive amination with an appropriately substituted 4-aminopiperidine.

Typically, 1,3-dibromo-5-fluorobenzene, benzophenone imine, Pd₂(dba)₃,BINAP and sodium t-butoxide are mixed in a suitable solvent, such astoluene, xylene, 1,4-dioxane, or the like, and heated, as for examplebetween 60-130° C. for about 8-20 hr., say about 15 hr. The reaction isquenched with saturated NaHCO₃ solution extracted several times with anorganic solvent, such as ethylacetate, methylene dichloride, or thelike. The organic layers are combined and the solvent removed. Theresidue is dissolved in a suitable solvent, such as THF, ether,methanol, or the like, and aqueous HCl is added, as for example, between1-6 N HCl, say about 5 N HCl. The reaction mixture is stirred for about1-3 hr. at between about 0-60° C., say about ambient temperature. Thereaction mixture is then diluted with dilute aqueous HCl and extractedwith an ethyl acetate/hexanes solvent system, or equivalent. The organiclayer is washed with dilute aqueous HCl and the aqueous layer is thenbasified with NaOH and extracted with an organic solvent such asmethylene dichloride or the like. The extract is dried, filtered,concentrated, and further purified by chromatography to give the diaminointermediate.

A mixture of the diamino intermediate and the desired R¹-acylchloride inan appropriate solvent, such as dioxane, pyridine, THF, or DMF, with anappropriate tertiary amine, such as triethylamine, N-methylmorpholine,or diisopropylethylamine is stirred at between about 0-40° C. until thereaction is complete, as for example, between about 2-20 hr., say about12 hr. The reaction is then quenched by addition of dilute aqueous NaOH.Normal work up and purification procedures provides the amideintermediate. Sodium triacetoxyborohydride is then added to a mixture ofthe amide intermediate, the appropriate 1-substituted or N-protected4-piperidone, acetic acid, and a molecular sieve (typically about 4 Å),in an appropriate solvent, such as THF, dichloroethane, methylenedichloride, or the like. The reaction mixture is stirred for about 8-20hr., say about 12 hr., at about 0-40° C., say about ambient temperature.The reaction is then quenched with dilute aqueous NaOH, extracted with asuitable organic solvent, such as methylene dichloride, ethylacetate, orthe like. The organic layer is dried, filtered, concentrated, andfurther purified, as for example, by chromatography, to provide thedesired product. When R⁷ is a protecting group, an appropriateunprotecting method is used to provide compounds wherein R² is hydrogen.If desired, the unsubstituted piperidinyl moiety can then be alkylatedby common reductive alkylation methods to provide compounds having R²other than hydrogen.

Scheme 8:

2,6-Dihalopyridine (X=Cl or Br) is alkylated with an appropriatelysubstituted 4-(methylamino)piperidine in the presence of a base such aspotassium carbonate, n-butyllithium, sodium hydride, etc. in DMF,acetonitrile, THF, or like solvent. Alternatively, the2,6-dihalopyridine can be treated with BINAP (or other acceptableligand), Pd(OAc)₂, the piperidine, and sodium tert-butoxide (or othersuitable base) in toluene (or like solvent) to yield the intermediate1-methyl-4-(N-(6-halopyridinyl)methylaminopiperidine. The halopyridineis then treated with BINAP (or other acceptable ligand), Pd(OAc)₂,benzophenone imine (or other amine equivalent), and sodium tert-butoxide(or other suitable base) in toluene (or like solvent) to yield theintermediate substituted 4-(N-(6-aminopyridinyl)methylaminopiperidine.This amine is then acylated with a variety of acid chlorides inpyridine, THF, 1,4-dioxane, or like solvent to yield the final product.Similarly, compounds wherein R⁵ is ethyl or propyl can be made using theappropriate 4-(ethylamino)piperidine or 4-(propylamino)piperidine.

Scheme 9:

Typically, a mixture of R¹-acyl chloride and 2,6-diaminopyridine in asuitable solvent, such as dioxane, THF, DMF, or the like, is stirred atabout ambient temperature to about 100° C. for between about 2-20 hr.,say about 12 hr. Normal work procedures, such as extraction, filtration,and/or chromatography, provide the N-(6-aminopyridin-2-yl)amideintermediate.

Sodium triacetoxyborohydride is then added to a mixture of the aboveintermediate with the appropriate 1-substituted 4-piperidone, aceticacid, and a molecular sieve, in an appropriate solvent, such as THF,dichloroethane, methylene dichloride, or the like. The reaction mixtureis stirred at between about 0-40° C., say about ambient temperature, forabout 8-20 hr., about 12 hr. Typically another aliquot of the piperidonereagent and sodium triacetoxyborohydride is added and allowed to reactwith any remaining N-(6-aminopyridin-2-yl)amide intermediate. Thereaction is then quenched with dilute aqueous NaOH. Routine work-up andpurification procedures provide the N-(5-pipieridin-4-ylamino)amidecompound. When R⁷ is the desired R² moiety, then normal finalpurification procedures are used to provide the end product. When R⁷ isa protecting group, the protecting group is removed by appropriateprocedures to provide compounds wherein R² is hydrogen. These compoundsmay, if desired, then be further alkylated by well know procedures toprovide end products wherein R² is other than hydrogen.

The following Preparations and Examples are provided to better elucidatethe practice of the present invention and should not be interpreted inany way so as to limit the scope thereof.

PREPARATIONS Preparation 1 N-(3-Aminophenyl)-2-chloro-4-fluorobenzamide

Combine 3-nitroaniline (3.0 g, 21.7 mmol), dichloromethane (100 mL),pyridine (2.11 mL, 26.0 mmol) and 2-chloro-4-fluorobenzoyl chloride(3.07 mL, 23.9 mmol). Stir at room temperature overnight. Filter thewhite precipitate, rinse with ether (2×10 mL), and dry under vacuum toprovide 2-chloro-4-fluoro-N-(3-nitrophenyl)benzamide (4.92 g, 77%).Combine the 2-chloro-4-fluoro-N-(3-nitrophenyl)benzamide (4.92 g, 16.7mmol) with ethanol (150 mL), SnCl₂-2H₂O (18.9 g, 83.6 mmol) andconcentrated hydrochloric acid (8.24 mL, 83.6 mmol). Stir at refluxunder a nitrogen atmosphere for 2 hr. Neutralize with ammonium hydroxide(15 mL). Filter through Celite®, wash with dichloromethane (2×15 mL),separate the filtrate, extract with dichloromethane (2×80 mL), and drythe combined organic layers over magnesium sulfate. Filter andconcentrate to dryness to provide the title intermediate as an off-whitesolid (3.04 g, 69%): mass spectrum (ion spray): m/z=265.0 (M+1); ¹H NMR(DMSO-d₆): 10.16 (bs, N—H), 7.60 (dd, J=6.2 Hz, 8.6 Hz, 1H), 7.54 (dd,J=2.5 Hz, 9.0 Hz, 1H), 7.30 (td, J=2.5 Hz, 8.5 Hz, 1H), 7.04 (t, J=2.0Hz, 1H), 6.93 (t, J=8.0 Hz, 1H), 6.74 (bd, J=7.9 Hz, 1H), 6.29 (dd,J=2.2 Hz, 7.9 Hz, 1H), 5.10 (bs, 2H).

Preparation 2 N-(3-Aminophenyl)-2-chloro-6-fluorobenzamide

Using a method similar to Preparation 1, using 2-chloro-6-fluorobenzoylchloride (1.0 g, 3.39 mmol) gives the title intermediate (820 mg, 91%):mass spectrum (ion spray): m/z=265.1 (M+1); ¹H NMR (DMSO-d₆): 10.42 (bs,N—H), 7.50 (td, J=6.2 Hz, 8.2 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.34 (t,J=8.7 Hz, 1H), 7.03 (t, J=2.1 Hz, 1H), 6.94 (t, J=8.0 Hz, 1H), 6.71 (dd,J=2.1 Hz, 8.0 Hz, 1H), 6.31 (dd, J=2.1 Hz, 8.0 Hz, 1H), 5.13 (bs, 2H).

Preparation 3 N-(3-Aminophenyl)-2,6-difluorobenzamide

Using a method similar to Preparation 1, using 2,6-difluorobenzoylchloride (1.0 g, 3.59 mmol) gives the title intermediate (723 mg, 81%):mass spectrum (ion spray): m/z=248.9 (M+1); ¹H NMR (DMSO-d₆): 10.44 (bs,N—H), 7.58-7.50 (m, 1H), 7.24-7.17 (m, 2H), 7.02 (t, J=2.0 Hz, 1H), 6.94(t, J=8.0 Hz, 1H), 6.72 (bd, J=8.0 Hz, 1H), 6.31 (dd, J=2.1 Hz, 8.0 Hz,1H), 5.14 (bs, 2H).

Preparation 4 N-(3-Aminophenyl)-2,4-difluorobenzamide

Using a method similar to Preparation 1, using 2,4-difluorobenzoylchloride (1.0 g, 3.59 mmol) gives the title intermediate (664 mg, 74%):mass spectrum (ion spray): m/z=248.9 (M+1); ¹H NMR (DMSO-d₆): 10.08 (bs,N—H), 7.68 (dd, J=8.1 Hz, 15.1 Hz, 1H), 7.38 (td, J=2.5 Hz, 10.2 Hz,1H), 7.18 (td, J=2.5 Hz, 8.5 Hz, 1H), 7.01 (bs, 1H), 6.93 (t, J=7.8 Hz,1H), 6.76 (bd, J=7.8 Hz, 1H), 6.29 (dd, J=1.9 Hz, 8.0 Hz, 1H), 5.10 (bs,2H).

Preparation 5 N-(3-Aminophenyl)-2,4,6-trifluorobenzamide

Using a method similar to Preparation 1, using 2,4,6-trifluorobenzoylchloride (1.0 g, 3.37 mmol) gives the title compound (485 mg, 54%): massspectrum (ion spray): m/z=266.9 (M+1); ¹H NMR (DMSO-d₆): 10.43 (bs,N—H), 7.34 (t, J=8.5 Hz, 2H), 6.99 (d, J=1.5 Hz, 1H), 6.94 (t, J=7.9 Hz,1H), 6.10 (d, J=8.2 Hz, 1H), 6.31 (d, J=8.2 Hz, 1H), 5.15 (bs, 2H).

Preparation 6 N-(3-Aminophenyl)-2-bromobenzamide

Using a method similar to Preparation 1, using 2-bromobenzoyl chloride(1.0 g, 3.11 mmol) gives the title intermediate (744 mg, 82%): massspectrum (ion spray): m/z=293.0 (M+1); ¹H NMR (DMSO-d₆): 10.14 (bs,N—H), 7.68 (d, J=8.0 Hz, 1H), 7.50-7.43 (m, 2H), 7.37 (td, J=2.5 Hz, 7.3Hz, 1H), 7.07 (bs, 1H), 6.92 (t, J=7.8 Hz, 1H), 6.74 (bd, J=8.0 Hz, 1H),6.29 (bd, J=8.0 Hz, 1H), 5.10 (bs, 2H).

Preparation 7 N-(3-Aminophenyl)-2-chlorobenzamide

Using a method similar to Preparation 1, using 2-chlorobenzoyl chloride(4.0 g, 14.5 mmol) gives the title intermediate (2.8 g, 78%): massspectrum (ion spray): m/z=247.0 (M+1); ¹H NMR (DMSO-d₆): 10.16 (bs,N—H), 7.54-7.39 (m, 4H), 7.06 (bs, 1H), 6.92 (t, J=8.0 Hz, 1H), 6.74(bd, J=8.0 Hz, 1H), 6.28 (bd, J=8.3 Hz, 1H), 5.10 (bs, 2H).

Preparation 8 N-(3-Aminophenyl)-2-trifluoromethoxybenzamide

Using a method similar to Preparation 1, using 2-trifluoromethoxybenzoylchloride (300 mg, 1.01 mmol) gives the title intermediate (274 mg, 69%)as a white foam: mass spectrum (ion spray): m/z=394.2 (M+1); ¹H NMR(CDCl₃): 8.18 (bs, N—H), 8.07 (d, J=7.5 Hz, 1H), 7.55 (t, J=7.7 Hz, 1H),7.45 (t, J=7.5 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.21 (s, 1H), 7.13 (t,J=8.0 Hz, 1H), 6.68 (d, J=7.7 Hz, 1H), 6.41 (d, J=8.0 Hz, 1H), 3.70-3.63(bm, 1H), 3.38-3.28 (bm, 1H), 3.85-3.77 (bm, 2H), 2.30 (s, 3H),2.21-2.04 (bm, 4H), 1.57-1.46 (bm, 2H).

Preparation 9 (3-(1-Methylpiperidin-4-ylamino)phenyl)carbamic acidtert-butyl ester

Add a solution of di-tert-butyl dicarbonate (5.04 g, 23.11 mmol) inchloroform (100 mL+100 mL rinse) to a solution of 1,3-phenylenediamine(5.0 g, 46.23 mmol) in chloroform (100 mL). Stir at room temperatureovernight. Wash with sodium hydroxide (1N aq., 200 mL) and separate theorganic layer. Purify through flash chromatography (ethylacetate/hexanes1/4 to 1/1) to provide (3-amino-phenyl)-carbamic acid tert-butyl ester(4.17 g, 87%).

Combine (3-aminophenyl)carbamic acid tert-butyl ester (0.156 g, 0.756mmol), 1-methylpiperidin-4-one (0.093 mL, 0.756 mmol), sodiumtriacetoxyborohydride (208 mg, 0.982 mmol), acetic acid (0.043 mL, 0.756mmol) and dichloromethane (8 mL). Stir at room temperature overnight.Dilute with dichloromethane (5 mL) and wash twice with sodium hydroxide(10 mL 1N aq.). Combine the organic layers and wash with saturatedaqueous NaCl (10 mL). Dry over magnesium sulfate, filter under reducedpressure and concentrate to dryness. Purify by flash chromatography on aBiotage® silica cartridge eluting with a 20/1 mixture of dichloromethaneand 2N ammonia in methanol to give the free base of the title compound.Dissolve the residue in diethyl ether and treat with ethereal hydrogenchloride. Triturate the resulting gum with ether to give the titlecompound as a white solid: mp 124-5° C.; mass spectrum (ion spray):m/z=306.2 (M+1), ¹H NMR (CDCl₃): 7.06 (t, J=8.0 Hz, 1H), 6.86 (bs, 1H),6.51-6.48 (m, 1H), 6.42 (bs, 1H), 6.30-6.27 (m, 1H), 3.60 (bs, 1H), 3.30(bs, 1H), 2.80 (bd, J=11.8 Hz, 2H), 2.31 (s, 3H), 2.19-2.02 (m, 4H),1.89 (bs, 2H), 1.52 (s, 9H).

Preparation 10 (3-(Methyl-(1-methylpiperidin-4-yl)amino)phenyl)carbamicacid tert-butyl ester

Combine (3-(1-methylpiperidin-4-ylamino)phenyl)carbamic acid tert-butylester (Preparation 9, 1.15 g, 3.77 mmol), methanol (15 mL) andformaldehyde (37% aq., 0.92 mL, 11.3 mmol). Stir at room temperature for45 min. Cool to 0° C. Add acetic acid (0.22 mL, 3.77 mmol) and sodiumcyanoborohydride (414 mg, 6.59 mmol). Stir at room temperatureovernight. Concentrate to dryness. Dissolve the residue in a 2/1 mixtureof ethyl acetate and hexanes (20 mL) and wash with sodium hydroxide (1Naq., 2×20 mL). Separate the organic layer and dry over magnesiumsulfate. Filter and concentrate under reduced pressure. Purify throughflash chromatography eluting with a 20/1 mixture of dichloromethane and2M ammonia in methanol to provide the title compound (990 mg, 82%): massspectrum (ion spray): m/z=320.3 (M+1).

Preparation 11 1-methyl-4-(N-(3-aminophenyl)-N-methylamino)piperidinetrihydrochloride

Combine acetyl chloride (5 mL) with dried methanol (10 mL) at 0° C.under nitrogen atmosphere. Stir for 1 hr. at 0° C. Add a solution of(3-(methyl-(1-methylpiperidin-4-yl)amino)phenyl)carbamic acid tert-butylester (Preparation 10, 990 mg, 3.1 mmol) in methanol (2 mL). Stirovernight. Concentrate under reduced pressure. Triture with diethylether (1 mL) to provide the title intermediate (671 mg, 66%): massspectrum (free base, ion spray): m/z=220.3 (M+1). Analysis calculatedfor C₁₃H₂₄Cl₃N₃Cl₃: C, 47.50; H, 7.36; N, 12.78. Found: C, 47.28; H,7.28; N, 12.46.

Preparation 12 4-(2-Hydroxyethyl)-1-isopropyl-1H-pyrazole

Combine 2,3-dihydrofuran (25 mL, 0.33 mol) and triethylorthoformate(93.3 mL, 0.56 mol) and then slowly add boron trifluoride diethyletherate (2.0 mL, 0.017 mol) while stirring rapidly. Allow the reactionto continue for 18 hr. Distill the reaction at 60° C. under 8 mm Hgvacuum to remove excess 2,3-dihydrofuran and triethylorthoformate. Heata portion of the remaining residue (10 g, 45 mmol) at reflux in 1 N HClwith isopropyl hydrazine (3.4 g, 45 mmol). After 2 hr, the temperatureis reduced to 80° C. and the reaction is stirred for 18 hr. Aftercooling to room temperature, the mixture is basified with 1 N NaOH to apH>12 and diluted with CH₂Cl₂. Separate and extract the aqueous layerwith CH₂Cl₂ (two times), combine organic layers, dry over MgSO₄, andconcentrate. Chromatography on silica gel, eluting with a gradient of0-10% (2M NH₃ in methanol) in CH₂Cl₂ provides the title intermediate asa brown solid (3.6 g, 52%). Mass spectrum (ion spray): m/z=155.2 (M+1);¹H NMR (DMSO, ppm) 7.52 (s, 1H), 7.24 (s, 1H), 4.59 (t, J=5.5, 10.6 Hz,1H), 4.39 (m, 1H), 3.51 (m, 2H), 2.51 (m, 2H), 1.38 (s, 3H), 1.35 (s,3H)

Preparation 13 2-Chloro-4-fluoro-N-(4-fluoro-3-nitrophenyl)benzamide

Combine 4-fluoro-3-nitroaniline (1.0 g, 6.4 mmol) with dioxane (20 mL).Treat mixture with 2-chloro-4-fluorobenzoyl chloride (1.6 g, 8.3 mmol).Stir the reaction overnight at room temperature. Transfer the reactionmixture into ethyl acetate (220 mL), then wash successively with aqueousHCl (1N, 50 mL), aqueous NaOH (1N, 50 mL), saturated aqueous NaCl (50mL). Dry the organic layer over anhydrous sodium sulfate, then evaporatethe solvent under reduced pressure. Further purify the residue bychromatography on silica gel, using a gradient of 10-30% ethyl acetatein hexanes to obtain the title intermediate (1.7 g, 85% yield): massspectrum (ion spray): m/z=313.0 (M+1).

Preparation 14 N-(3-Amino-4-fluorophenyl)-2-chloro-4-fluorobenzamide

Add 2-chloro-4-fluoro-N-(4-fluoro-3-nitrophenyl)benzamide (Preparation11, 1 g, 3.2 mmol) to a warm solution (55° C.) of SnCl₂.2H2O (3.6 g, 16mmol) in ethanol (25 mL). Add concentrated HCl (25 mL). Stir and heatthe mixture at 60° C. for 30 min. Cool and then basicify the mixture topH 14 with aqueous NaOH. Extract the product three times with ethylacetate (3×150 mL). Combine the organic layers and dry over anhydroussodium sulfate. Evaporate the solvent under reduced pressure. Furtherpurify the residue by chromatography on silica gel, using a gradient of10-50% ethyl acetate in hexanes to obtain the title intermediate (800mg, 89% yield): mass spectrum (ion spray): m/z=283.0 (M+1).

Preparation 15 2,4-Difluoro-N-(4-fluoro-3-nitrophenyl)benzamide

Using a method similar to Preparation 13, using 4-fluoro-3-nitroaniline(1.0 g, 6.4 mmol), dioxane (20 mL), and 2,4-difluorobenzoyl chloride(1.46 g, 8.3 mmol) gives the title intermediate (1.6 g, 84% yield): massspectrum (ion spray): m/z=297.0 (M+1).

Preparation 16 2,4-Difluoro-N-(3-amino-4-fluorophenyl)benzamide

Using a method similar to Preparation 14 using2,4-Difluoro-N-(4-fluoro-3-nitrophenyl)benzamide (Preparation 13) (1.0g, 3.38 mmol), SnCl₂.2H₂O (3.8 g, 16.9 mmol), ethanol (25 mL), andconcentrated HCl (25 mL), gives the title intermediate (803 mg, 89%yield): mass spectrum (ion spray): m/z=267.0 (M+1).

Preparation 17 1-Methyl-4-(3-nitrophenylamino)piperidine

Combine 3-nitroaniline (25.0 g, 180.0 mmol), 1-methyl-4-piperidone (40.9mL, 360.0 mmol), and acetic acid (21.7 mL, 360.0 mmol) in 350 mL ofdichloroethane. Stir at room temperature for 0.5 hr. Add sodiumtriacetoxyborohydride (76.4 g, 360.0 mmol) in several portions, and stirthe reaction mixture at room temperature for 2 days. Quench the reactionmixture by the addition of saturated aqueous NaHCO₃, and partitionbetween CH₂Cl₂ and water. Adjust aqueous phase to about pH 8, andextract 3 times with CH₂Cl₂. Combine the organic fractions and wash withsaturated aqueous NaCl, dry over MgSO₄, and concentrate. Further purifyby chromatography over silica gel, eluting with a gradient of 1-10%methanol in ethylacetate, to obtain the title intermediate (23.8 g, 56%yield): mass spectrum (ion spray): m/z=236.2 (M+1); Anal calc'd forC₁₂H₁₇N₃O₂.0.3H₂O: Theory: C, 59.88; H, 7.37; N, 17.45. Found: C, 60.07;H, 7.18; N, 17.09.

Alternatively, to a solution of 3-nitroaniline (360 g, 2.6 mol) indichloromethane (7.2 L) under nitrogen, add sodium triacetoxyborohydride(1.38 kg, 6.5 mol) by portion over 1 hr. Then add acetic acid (370 mL,6.5 mol) at a rate such that T_(mass) does not exceed 25° C., followedby 1-methyl 4-piperidone (450 g, 3.98 mol), which is introduced over 150min., keeping the temperature below 25° C. Stir the mixture at roomtemperature for 3 hr. Add additional sodium triacetoxyborohydride (280g, 1.32 mol), acetic acid (74 mL, 1.29 mol), and 1-methyl 4-piperidone(90 g, 0.8 mol) and stir the mixture overnight at room temperature.Quench the reaction mixture with water (4 L) and adjust the pH tobetween 8-9 with 30% sodium hydroxide. Extract the organic layer andwash the aqueous layer with dichloromethane (2 L). Wash the combinedorganic layers with water (1 L), dry over MgSO₄ (100 g) and concentrate(2×). Filter the resulting suspension, wash with dichloromethane (500mL), and concentrate the filtrates under reduced pressure (40° C.) toprovide the crude 1-methyl-4-(3-nitrophenylamino)piperidine as an orangesolid (620 g). Suspend the crude1-methyl-4-(3-nitrophenylamino)piperidine (590 g) in a mixture of water(5.9 L) and isopropanol (590 mL). Stir the mixture at room temperaturefor 5 hr. Filter the resulting yellow crystals, rinse with a mixture ofwater (600 mL) and isopropanol (60 mL) and the dry under reduce pressureat room temperature overnight to provide1-methyl-4-(3-nitrophenylamino)piperidine (524 g, 94% yield).

Preparation 18 1-Methyl-4-(3-aminophenylamino)piperidine triacetate

Combine 1-methyl-4-(3-nitrophenylamino)piperidine (Preparation 17) (8.2g, 34.8 mmol), acetic acid (6.3 g, 110 mmol), and palladium on carbon(10%, 2.1 g) in 300 mL of ethanol. Evacuate the reaction flask, chargewith H₂ gas (atmospheric pressure) and stir at room temperature for 18hr. Filter through Celite®, rinse with ethylacetate, and concentrate toprovide 13.1 g of the title intermediate, which is typically used insubsequent reactions without further purification. A small sample of thefree base amine further purified by dissolving the triacetate salt wasdissolved in methanol, placing on a 1 g SCX column (mega bond elut®,Varian), and washing with methanol, eluting with 2 M NH₃ in methanol,and concentrated in vacuo: mass spectrum (ion spray): m/z=206.2 (M+1);¹H NMR δ (CDCl₃, ppm) 6.93 (t, J=7.9, 15.8 Hz, 1H), 6.03 (d, J=7.9 Hz,2H), 5.94 (s, 1H), 3.46 (bs, 3H), 3.24 (bs, 1H), 2.79 (m, 2H), 2.28 (s,3H), 2.10 (m, 4H), 1.40 (m, 2H).

Alternatively, charge a 2 L Parr bottle with1-methyl-4-(3-nitrophenylamino)piperidine (100 g; 0.425 mol), 10% Pd/C(5 g) and methanol (1 L). Shake the mixture overnight under an initialhydrogen pressure of 4 atm, keeping the temperature below 35° C. Filteroff the catalyst and wash with methanol (100 mL). Concentrate thefiltrates under reduced pressure to provide1-methyl-4-(3-aminophenylamino)piperidine as a red oil (95.7 g, 100%yield) which crystallizes upon standing at room temperature.

Preparation 19 1-Methyl-4-(3-chloro-2-fluorophenylamino)piperidine

Combine 3-chloro-2-fluoroaniline (4.37 g, 30 mmol),1-methylpiperidin-4-one (3.39 g, 30 mmol), sodium triacetoxyborohydride(5.26 g, 33 mmol), and acetic acid (5.4 g, 90 mmol) and stir at roomtemperature overnight. Partition the reaction mixture betweendichloromethane and saturated aqueous NaCl containing NH₄OH, dry overanhydrous sodium sulfate, evaporate and purify on a silica gel column(110 g), using a gradient of dichloromethane-2M NH₃ in methanol to give2.34 g of the title compound (32% yield): mass spectrum (ion spray):m/z=243 (M+1); ¹H NMR (CDCl₃): 6.88 (ddd, 1H), 6.63 (ddd, 1H), 6.56 (dd,1H), 3.85 (br d, 1H), 3.28 (m, 1H), 2.80 (m, 2H), 2.30 (s, 3H), 2.13 (m,2H), 2.04 (m, 1H), 1.53 (m, 2H). (file: mn4-b6k-284-2)

Preparation 20 2-Fluoro-N-(1-methylpiperidin-4-yl)benzene-1,3-diamine

Combine 1-methyl-4-(3-Chloro-2-fluorophenylamino)piperidine (Preparation19) (0.439 g, 1.8 mmol), benzophenone imine (0.393 g), Pd₂(dba)₃ (4.1mg), 2-(dicyclohexylphosphino) biphenyl (4.7 mg), and sodium t-butoxide(0.242 g) with toluene (5 mL) and heat at reflux overnight. Dissolve thereaction mixture in methanol and filter through a SCX column (10 g),wash with methanol, elute the product with 2M NH₃ in methanol, evaporatethe solvent, and further purify on a silica gel column (35 g, using adichloromethane-2M NH₃ in methanol gradient) to give crude1-methyl-4-(3-benzhydrylideneamino-2-fluorophenylamino)piperidine (0.372g). Add 1N HCl (2 mL) into a solution of the benzhydrylidenylintermediate in THF (10 mL) and stir at room temperature for 30 minutes.Basicify with NH₄OH, extract with ethyl acetate, dry over anhydroussodium sulfate, evaporate and purify on a silica gel column (10 g),using a gradient of dichloromethane-2M NH₃ in methanol to give the titleintermediate (0.08 g): mass spectrum (ion spray): m/z=224 (M+1); ¹H NMR(CDCl₃): 6.75 (ddd, 1H), 6.12 (m, 2H), 3.70 (bd, 1H), 3.62 (br s, 2H),3.25 (m, 1H), 2.80 (m, 2H), 2.29 (s, 3H), 2.10 (m, 4H), 1.53 (m, 2H).

Preparation 211-Methyl-4-(N-(3-chloro-2-fluorophenyl)methylamino)piperidine

Mix 1-methyl-4-(3-chloro-2-fluorophenylamino)piperidine (Preparation 19)(0.961 g), formaldehyde (37%) (0.973 g), sodium cyanoborohydride (0.917g) and acetic acid (1.66 g) in methanol (50 mL) and stir at roomtemperature overnight. Add formaldehyde (37%) (0.973 g), sodiumcyanoborohydride (0.917 g) and acetic acid (2 mL) and stir at roomtemperature overnight. Partition the reaction mixture betweendichloromethane and saturated aqueous NaCl, dry over anhydrous sodiumsulfate, evaporate and purify on a silica gel column, using a gradientof dichloromethane-2M NH₃ in methanol to give 1.06 g of the titleintermediate.

Preparation 221-Methyl-4-(N-(3-amino-2-fluorophenyl)methylamino)piperidine

Heat a mixture of1-methyl-4-(N-(3-chloro-2-fluorophenyl)methylamino)piperidine(Preparation 21) (0.77 g), benzophenone imine (0.652 g), Pd₂(dba)₃ (6.9mg), racemic BINAP (7.9 mg) and sodium t-butoxide (0.404 g) in toluene(10 mL) for 44 hours. Dilute the reaction mixture with methanol, load ona SCX column (10 g), wash with methanol, elute the product with 2M NH₃in methanol, evaporate and purify on a silica gel column (110 g), usinga gradient of dichloromethane-2M NH₃ in methanol to give 0.21 g of1-methyl-4-(N-(3-benzhydrylidenylamino-2-fluorophenyl)methylamino)piperidine.

Add 2 mL of 1N HCl into a solution of the diamine (0.21 g) and stir for30 min, basicify with NH₄OH, extract with ethyl acetate, dry overanhydrous sodium sulfate, evaporate and purify on a silica gel column(10 g), using a gradient of dichloromethane-2M NH₃ in methanol to give44 mg of the title intermediate.

Preparation 23 1-Methyl-4-(N-(2-fluorophenyl)methylamino)piperidine

Mix 1-bromo-2-fluorobenzene (3.50 g), 1-methyl-4-(methylamino)piperidine(2.56 g), Pd₂(dba)₃ (0.366 g), racemic BINAP (0.498 g) and sodiumt-butoxide (2.70 g) in toluene (40 mL) and heat at reflux for two days.Filter through a Celite® bed, partition between dichloromethane andsaturated aqueous NaCl, dry over anhydrous sodium sulfate, evaporate andpurify on a silica gel column (35 g), using a gradient ofdichloromethane-2M NH₃ in methanol to give 1.1 g of the titleintermediate.

Preparation 241-Methyl-4-(N-(2-fluoro-3-bromophenyl)methylamino)piperidine

Add n-butyl lithium (1.6 M in hexanes, 4.3 mL) into a solution of2,2,6,6-tetramethyl-piperidine (0.97 g) in THF (10 mL) at −78° C. andstir for 30 minutes. Add a solution of1-methyl-4-(N-(2-fluorophenyl)methylamino)piperidine (Preparation 23,1.02 g) in THF (10 mL) portion wise and stir for 10 minutes. Add1,2-dibromo-1,1,2,2-tetrachloroethane (1.50 g) in THF (10 mL) dropwiseand stir for 1 hr. Remove the cooling bath and stir for 30 minutes.Partition between ethyl acetate and saturated aqueous NaCl, dry overanhydrous sodium sulfate, evaporate and purify on a silica gel column(110 g), using a gradient of dichloromethane-2M NH₃ in methanol to give0.49 g of the title intermediate.

Preparation 251-Methyl-4-(N-(2-fluoro-3-aminophenyl)methylamino)piperidine

Mix 1-methyl-4-(N-(2-fluoro-3-bromophenyl)methylamino)piperidine(Preparation 24, 0.42 g), benzophenone imine (0.303 g), Pd₂(dba)₃ (25mg), racemic BINAP (35 mg) and sodium t-butoxide (0.187 g) in toluene(10 mL) and heat at reflux for 3 hours. Dilute the reaction mixture withmethanol (5 mL), load on a SCX column (10 g), wash with methanol, elutethe with 2M NH₃ in methanol, evaporate and further purify on a silicagel column (10 g), using a gradient of dichloromethane-2M NH₃ inmethanol to give 0.44 g of the title intermediate.

Preparation 261-Methyl-4-(N-(2-fluoro-3-chlorophenyl)ethylamino)piperidine

Add acetaldehyde (0.817 g) to a solution of1-methyl-4-(3-chloro-2-fluorophenylamino)piperidine (Preparation 19)(0.45 g), sodium cyanoborohydride (0.123 g) and trifluoroacetic acid(0.633 g) in methanol (20 mL) and heat in a sealed tube at 80° C. forthree days. Load on a SCX column (10 g), wash with methanol, elute with2M NH₃ in methanol, evaporate, and further purify on a silica gel column(35 g), using a gradient of dichloromethane-2M NH₃ in methanol to give0.50 g of the title intermediate as a colorless oil: mass spectrum(electric spray) m/z=271 (M+1); ¹H NMR (CDCl₃): 6.94 (m, 3H), 3.14 (q,J=7.0 Hz, 2H), 3.06 (m, 1H), 2.84 (br d, 2H), 2.22 (s, 3H), 1.93 (m,2H), 1.74 (m, 4H), 0.95 (t, J=7.0 Hz, 3H).

Preparation 271-Methyl-4-(N-(2-fluoro-3-aminophenyl)ethylamino)piperidine

Mix 1-methyl-4-(N-(2-fluoro-3-chlorophenyl)ethylamino)piperidine(Preparation 26) (0.367 g), benzophenone imine (0.295 g), Pd₂ (dba)₃ (50mg), 2-(di-t-butylphosphino)biphenyl (32 mg), and sodium t-butoxide(0.182 g) in toluene (10 mL) and heat at reflux for three days. Dilutewith methanol (5 mL), 30 minutes after adding 2 mL of 5N HCl, load on aSCX column (10 g), wash with methanol, elute the product with 2M NH₃ inmethanol, evaporate and purify on a silica gel column (35 g), using agradient of dichloromethane-2M NH₃ in methanol to give 39 mg of thetitle compound: mass spectrum (electric spray) m/z=252 (M+1).

Preparation 281-Methyl-4-(N-(3-nitro-5-fluorophenyl)methylamino)piperidine

Combine 1,3-difluoro-5-nitro-benzene (1.78 mL, 15.7 mmol),1-methyl-4-(methylamino)piperidine (2.74 mL, 18.85 mmol), sodium acetate(2.45 g, 29.8 mmol) and absolute ethanol (10 mL) in a sealed tube. Heatand stir at 100° C. for 16 hr. Cool the reaction mixture to ambienttemperature and pour into water (100 mL). Extract with ethyl acetate(2×100 mL). Wash combined organic layers with saturated aqueous NaClsolution (100 mL), dry over sodium sulfate, filter, and concentrate.Purify residue by silica gel flash chromatography eluting with 10% (2MNH₃ in methanol) in CH₂Cl₂ to obtain 0.06 g (1.4%) of the titleintermediate: ¹H NMR (CDCl₃): 7.3 (m, 1H), 7.2 (m, 1H), 6.7 (m, 1H), 3.6(m, 1H), 3.0 (m, 2H), 2.8 (s, 3H), 2.3 (s, 3H), 2.2 (m, 2H), 1.9 (m,2H), 1.7 (m, 2H).

Preparation 291-Methyl-4-(N-(3-amino-5-fluorophenyl)methylamino)piperidine

Combine 1-methyl-4-(N-(3-nitro-5-fluorophenyl)methylamino)piperidine(Preparation 28) (0.06 g, 0.22 mmol), iron dust (0.06 g, 1.12 mmol),methanol (5 mL) and 1M HCl (0.22 mL, 0.22 mmol), stir, and heat atreflux for 18 hr. Cool the reaction mixture to ambient temperature,dilute with ethyl acetate (50 mL), and add 1N sodium hydroxide solutionuntil basic (pH=9). Separate organic layer, wash with saturated aqueousNaCl solution, dry over sodium sulfate, filter, and concentrate toobtain 0.036 g (69%) of the title intermediate: ¹H NMR (CDCl₃): 5.9 (m,1H), 5.7 (m, 2H), 3.6 (bs, 2H), 3.4 (m, 1H), 2.9 (m, 2H), 2.7 (s, 3H),2.3 (s, 3H), 2.0 (m, 2H), 1.8 (m, 2H), 1.7 (m, 2H).

Preparation 301-Methyl-4-(N-(3-bromo-5-fluorophenyl)methylamino)piperidine

Combine 1,3-dibromo-5-fluorobenzene (5.0 g, 19.7 mmol),1-methyl-4-(methylamino)piperidine (2.58 mL, 17.7 mmol),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.49 g, 0.79 mmol), sodiumt-butoxide (2.57 g, 27.58 mmol) and toluene (100 mL), stir and heat at80° C. After 10 minutes, add Pd₂(dba)₃ (0.49 g, 0.79 mmol). After 3 hr.at 80° C., cool to ambient temperature. Dilute with ethyl acetate (100mL) and wash with water (50 mL). Dry the organic layer over sodiumsulfate, filter, and concentrate to an oil. Purify the residue by silicagel flash chromatography eluting with 10% (2M NH₃-methanol) in CH₂Cl₂ toobtain 2.95 g (55%) of the title intermediate: ¹H NMR (CDCl₃): 6.6 (s,1H), 6.5 (m, 1H), 6.3 (m, 1H), 3.5 (m, 1H), 2.9 (m, 2H), 2.7 (s, 3H),2.3 (s, 3H), 2.0 (m, 2H), 1.8 (m, 2H), 1.7 (m, 2H).

Preparation 311-Methyl-4-(N-(3-amino-5-fluorophenyl)methylamino)piperidine

Combine 1-methyl-4-(N-(3-bromo-5-fluorophenyl)methylamino)piperidine(Preparation 30, 2.90 g, 9.63 mmol), benzophenone imine (1.94 mL, 11.55mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.24 g, 0.39 mmol),sodium t-butoxide (1.26 g, 13.48 mmol), and toluene (60 mL), stir andheat to 80° C. After 10 minutes, add Pd₂(dba)₃ (0.17 g, 0.19 mmol).After 3 hr at 80° C., cool to ambient temperature. Dilute with ethylacetate (100 mL) and wash with water (50 mL). Separate organic layer,dry over sodium sulfate, filter and concentrate. Dissolve this materialin tetrahydrofuran (120 mL) and treat with 1M aqueous hydrochloric acidsolution (40 mL). After stirring at ambient temperature for 1 hr, add 2Msodium hydroxide solution until basic (21 mL). Extract with ethylacetate (2×100 mL). Wash organic layer with saturated aqueous NaClsolution (75 mL), dry over sodium sulfate, filter and concentrate to anoil. Purify residue by silica gel flash chromatography eluting with 10%(2M NH₃ in methanol) in CH₂Cl₂ to obtain 1.96 g (86%) of the titlecompound.

Preparation 32 1,3-Diamino-5-fluorobenzene

Add 1,3-dibromo-5-fluorobenzene (5.078 g, 20 mmol), benzophenone imine(8.700 g, 48 mmol), Pd₂(dba)₃ (366 mg, 0.4 mmol), BINAP (747 mg, 1.2mmol) and sodium t-butoxide (4.998 g, 52 mmol) to toluene (100 mL). Heatthe reaction mixture at 80° C. for 15 hr. Quench the reaction withsaturated NaHCO₃ solution. Extract the mixture with ethylacetate threetimes. Wash the combined organic layers with saturated NaCl solution,dry over Na₂SO₄, filter and concentrate to give a residue. Dissolve theresidue in THF (80 mL), add 5N HCl (14 mL), and stir for 2 hr. Dilutethe reaction mixture with 0.1N HCl and extract with ethylacetate/hexanes(1:2) twice. Wash the combined organic layer once with 0.1N HCl, combinethe aqueous layers, adjust to pH>11 with 5N NaOH. Extract the turbidmixture with CH₂Cl₂ three times. Combine the organic layers, dry overNa₂SO₄, filter, and concentrate to give an orange-color oil. Purify bychromatography on silica gel, eluting with 30-60% ethylacetate inhexanes to obtain the title intermediate as a yellow oil (1.955 g, 77%):mass spectrum (ion spray): m/z=127.1 (M+1), ¹H NMR (CDCl₃, ppm): 5.82(m, 3H), 3.67 (s, br, 2H).

Preparation 33 1-Methyl-4-(N-(6-bromopyridinyl)methylaminopiperidine

Dissolve 2,6-dibromopyridine (5.0 g, 21.1 mmol), (±)-BINAP (1.09 g, 1.76mmol), and Pd₂(dba)₃ (805 mg, 0.88 mmol) in toluene (50 mL). Stir andadd 1-methyl-4-(methylamino)piperidine (2.56 mL, 17.6 mmol) followed bysodium t-butoxide (2.37 g, 24.6 mmol). Heat the reaction mixture to 80°C. for 40 hr. Cool the reaction mixture to room temperature andpartition between ethyl acetate and water. Separate the organic layer,and extract the aqueous layer with dichloromethane (2×50 mL). Combinethe organic extracts, dry over MgSO₄, filter, and concentrate in vacuo.Load residue onto an SCX column and wash with methanol. Elute with 2Mammonia in methanol and concentrate in vacuo. Further purify the productby column chromatography on silica gel using a gradient of 2%-10% (2MNH₃ in methanol) in CH₂Cl₂) to give of the title intermediate (632 mg,13%): mass spectrum (ion spray): m/z 286.0 (M+1); ¹H NMR: δ (CDCl₃, ppm)7.25 (m, 1H), 6.65 (d, J=8.0 Hz, 1H), 6.35 (d, J=8.4 Hz, 1H), 4.37 (m,1H), 2.94 (m, 2H), 2.85 (s, 3H), 2.30 (s, 3H), 2.13 (m, 2H), 1.85 (m,2H), 1.68 (m, 2H).

Preparation 34 1-Methyl-4-(N-(6-aminopyridinyl)methylaminopiperidine

Mix 1-methyl-4-(N-(6-bromopyridinyl)methylaminopiperidine (1.02 g, 3.59mmol) (Preparation 33), (±)-BINAP (224 mg, 0.36 mmol), and Pd₂(dba)₃(164 mg, 0.18 mmol) in toluene (20 mL). Add benzophenone imine (723 μL,4.31 mmol) and sodium tert-butoxide (483 mg, 5.03 mmol) to the reactionand heat to 80° C. for 19 hr. Cool the reaction mixture to roomtemperature and partition between ethyl acetate and water. Separate theorganic layer, and extract the aqueous layer with dichloromethane (2×50mL). Combine the organic extracts, dry (MgSO₄), filter, and concentratein vacuo. Dissolve the residue in 50 mL of 1:1 THF/H₂O and treat with 50mL of aqueous 1N HCl for 2 hr. Load the solution onto an SCX column, andwash successively with 1:1 THF/H₂O, methanol, and finally with 2Mammonia in methanol. Concentrate the basic wash in vacuo, and purify theresidue by column chromatography on silica gel using a gradient of2%-10% (2M NH₃ in methanol) in CH₂Cl₂ to give of the title intermediate(459 mg, 58%): mass spectrum (ion spray): m/z=221.2 (M+1), AnalysisCalcd for C₁₂H₂₀N₄.0.1 CH₂Cl₂: C, 63.51; H, 8.90; N, 24.49. Found: C,63.42; H, 8.56; N, 24.25.

Preparation 351-Methyl-4-(N-(6-chloropyridin-2-yl)methylamino)piperidine

Dissolve 1-methyl-4-(methylamino)piperidine (10 mL, 68.8 mmol) intetrahydrofuran (50 mL) and cool to −78° C. Slowly add n-butyllithium(1.6 N in hexane, 43 mL, 68.8 mmol) to the reaction mixture and stir at−78° C. for 30 min. Warm the reaction mixture to room temperature andstir for 30 min. Then cool the reaction mixture to −78° C. and add2,6-dichloropyridine (11.2 g, 75.7 mmol) in tetrahydrofuran (50 mL).Stir the reaction mixture at −78° C. for 15 min, warm to roomtemperature, and then heat to 60° C. for 19 hr. Cool the reactionmixture to room temperature and partition between ethyl acetate andwater. Separate the organic layer and extract the aqueous layer withdichloromethane (2×50 mL). Combine organic extracts, dry (MgSO₄),filter, and concentrate in vacuo. Purify the residue by columnchromatography on silica gel using a gradient of 2%-10% (2M NH₃ inmethanol) in CH₂Cl₂ to give of the title intermediate (11.91 g, 72%):mass spectrum (ion spray): m/z=240.1 (M+1); ¹H NMR: δ (CDCl₃, ppm) 7.34(t, J=7.6, 16.0 Hz, 1H), 6.50 (d, J=8.0 Hz, 1H), 6.33 (d, J=8.8 Hz, 1H),4.41 (m, 1H), 2.94 (m, 2H), 2.86 (s, 3H), 2.32 (s, 3H), 2.15 (m, 2H),1.84 (m, 2H), 1.68 (m, 2H).

Preparation 36 1-Methyl-4-(N-(6-aminopyridine) methylamino)piperidine

Place 1-methyl-4-(N-(6-chloropyridin-2-yl)methylamino)piperidine(Preparation 35, 1.62 g, 6.76 mmol), (±)-BINAP (420 mg, 0.68 mmol), andPd₂(dba)₃ (310 mg, 0.34 mmol) in toluene. (15 mL). Add benzophenoneimine (1.36 mL, 8.11 mmol) and sodium tert-butoxide (910 mg, 9.46 mmol)to the reaction and heat to 80° C. for 20 hr. Cool the reaction to roomtemperature and partition between ethyl acetate and water. Separate theorganic layer, and extract the aqueous layer with dichloromethane (2×50mL). Combine the organic extracts, dry over MgSO₄, filter, andconcentrate in vacuo. Load the residue on an SCX column, wash withmethanol, elute with 2M ammonia in methanol, and concentrate in vacuo.Dissolve the residue in 50 mL of 1:1 THF/H₂O and treat with 50 mL of 1NHCl for 2 hr. Load the solution onto an SCX column, and washsuccessively with 1:1 THF/H₂O, methanol, and finally with 2M ammonia inmethanol. Concentrate the basic wash in vacuo, and purify the residue bycolumn chromatography on silica gel using a gradient of 2%-10% (2M NH₃in methanol) in CH₂Cl₂ to give of the title intermediate (1.38 g, 93%):mass spectrum (ion spray): m/z=221.1 (M+1); ¹H NMR: δ (CDCl₃, ppm) 7.23(t, J=9.2, 17.2 Hz, 1H), 5.86 (d, J=8.0 Hz, 1H), 5.78 (d, J=7.2 Hz, 1H),4.46 (m, 1H), 4.13 (bs, 2H), 2.94 (m, 2H), 2.81 (s, 3H), 2.31 (s, 3H),2.11 (m, 2H), 1.84 (m, 2H), 1.65 (m, 2H).

Preparation 37 N-(6-Aminopyridin-2-yl)-4-fluorobenzamide

Combine triethylamine (15.8 mL, 111.0 mmol) and 2,6-diaminopyridine (6.5g, 59.6 mmol) in dioxane (200 mL). Add 4-fluorobenzoyl chloride (5.46mL, 44.7 mmol) in small increments. After complete addition, stir atroom temperature for 18 hr. Pour into water and dilute with ethylacetate and water. Separate and extract twice the aqueous layer withCH₂Cl₂, combine the organic fractions, dry over MgSO₄, and concentrate.Chromatograph on silica gel, eluting with a gradient of 0%-10% (2M NH₃in methanol) in CH₂Cl₂ to give the title intermediate (8.91 g, 86.3%):mass spectrum (ion spray): m/z=232.3 (M+1); Analysis calculated forC₁₂H₁₀N₃OF 0.1H₂O: C, 61.85; H, 4.41; N, 18.03. Found: C, 61.75; H,4.08; N, 17.66.

Preparation 38 N-(6-Aminopyridin-2-yl)-2-chloro-4-fluorobenzamide

Using a method similar to Preparation 37, using 2-chloro-4-fluorobenzoylchloride, gives the title intermediate as a tan solid: mass spectrum(ion spray): m/z=266.2 (M+1); Analysis calculated for C₁₂H₉N₃OClF: C,54.25; H, 3.41; N, 15.82. Found: C, 53.98; H, 3.23; N, 15.54.

Preparation 394-(6-(4-Fluorobenzoylamino)pyridin-2-ylamino)piperidine-1-carboxylicacid t-butyl ester

Place N-(6-aminopyridin-2-yl)-4-fluorobenzamide (Preparation 37) (2 g,8.3 mmol) and 1-boc-4-piperidone (15.0 g, 83 mmol) in 1,2-dichloroethane(20 mL). Stir for 1 hr. then add sodium triacetoxyborohydride (4.38 g,20.8 mmol). After stirring for 36 hr., quench with 1 N NaOH and dilutewith CH₂Cl₂. Separate and extract the aqueous layer twice with CH₂Cl₂,combine organics, dry over MgSO₄, and concentrate. Take up the residuein CH₂Cl₂, and place on two 10 g SCX columns. Wash the columnssuccessively with CH₂Cl₂ and then with methanol. Elute the product with2M NH₃ in methanol. Concentrate and chromatograph on silica gel, elutingwith a gradient of 0-10% (2M NH₃ in methanol) in CH2Cl2) to give thetitle intermediate 3.11 g (90%): mass spectrum (ion spray): m/z 415.4(M+1); mp 82.7° C.

Preparation 404-(6-(2-Chloro-4-fluorobenzoylamino)pyridin-2-ylamino)piperidine-1-carboxylicacid tert-butyl ester

Using a method similar to Preparation 39, usingN-(6-aminopyridin-2-yl)-2-chloro-4-fluorobenzamide (Preparation 38, 2.0g, 7.5 mmol), gives the title intermediate as a white solid: massspectrum (ion spray): m/z=449.4 (M+1); mp 82.0° C.

Preparation 414-((6-(4-Fluorobenzoylamino)pyridin-2-yl)methylamino)piperidine-1-carboxylicacid tert-butyl ester

Place4-(6-(4-fluorobenzoylamino)pyridin-2-ylamino)piperidine-1-carboxylicacid t-butyl ester (Preparation 39) (3.1 g, 7.4 mmol) and formaldehyde(37% in water) (6.1 mL, 74 mmol) in methanol (10 mL) and stir for 36 hr.Add sodium cyanoborohydride (2.3 g, 37.0 mmol) and stir for 2 hr. Quenchthe reaction with 1N NaOH and dilute with CH₂Cl₂. Separate and extractthe aqueous layer twice with CH₂Cl₂, and once with 3:1CHCl₃:isopropanol. Combine the organic fractions, dry over MgSO₄, andconcentrate. Chromatograph on silica gel, eluting with a gradient of0-10% (2M NH₃ in methanol) in CH₂Cl₂ to give the title intermediate(0.97 g, 30.6%): mass spectrum (ion spray): m/z=429.4 (M+1); mp 77.7° C.

Preparation 424-((6-(2-Chloro-4-fluorobenzoylamino)pyridin-2-yl)methylamino)piperidine-1-carboxylicacid tert-butyl ester

Using a method similar to Preparation 41, using4-(6-(2-chloro-4-fluorobenzoylamino)pyridin-2-ylamino)piperidine-1-carboxylicacid t-butyl ester (Preparation 40, 2.11 g, 4.6 mmol), gives the titleintermediate as a white solid: mass spectrum (ion spray): m/z=463.3(M+1); mp 79.1° C.

Preparation 43 N-(6-Aminopyridin-2-yl)-2,4,6-trifluorobenzamide

Combine 2,4,6-trifluorobenzoyl chloride (3.891 g, 20 mmol),2,6-diaminopyridine (6.548 g, 60 mmol) and dioxane (25 mL) and stir for1 hr. at room temperature followed by heating at 40° C. overnight.Dilute the reaction mixture with CH₂Cl₂ (100 mL), and wash with 0.1NNaOH solution. Extract the aqueous layer three times with CH₂Cl₂.Combine the organic layers, dry over Na₂SO₄, filter, and concentrate toa residue. Chromatography on silica gel, eluting with a gradient of40-50% ethylacetate in hexanes gives the title intermediate (3.95 g,74%): mass spectrum (ion spray): m/z=267.9 (M+1); ¹H NMR (CDCl₃, ppm):8.28 (s, br, 1H), 7.66 (d, 1H), 7.52 (t, 1H), 6.78 (m, 2H), 6.31 (d,1H), 4.36 (s, br, 2H).

Preparation 44 N-(6-Amino-pyridin-2-yl)acetamide

Dissolve 2,6-diaminopyridine (9.822 g, 90 mmol) in dioxane (100 mL) andcool to 0° C. Add acetyl chloride (2.355 g, 2.1 mL, 30 mmol) slowly andstir for 1 hr. at 0° C. Remove the ice bath and stir at room temperatureovernight. Quench the reaction mixture with saturated NaHCO₃ solution,extract with ethyl acetate three times. Combine the organic layers, dryover Na₂SO₄, filter, and concentrate to give a solid. Chromatography onsilica gel, eluting with a gradient of 60-70% ethylacetate in hexanesaffords the title intermediate (3.45 g, 76%): mass spectrum (ion spray):m/z=152.1 (M+1); ¹H NMR (CDCl₃, ppm): 7.49 (m, 3H), 6.28 (d, 1H), 4.31(s, br, 2H), 2.19 (s, 3H).

Preparation 45 N-(6-Aminopyridin-2-yl)-2-chlorobenzamide

Using a method similar to Preparation 44, using 2-chlorobenzoyl chloride(875 mg, 5.0 mmol) gives the title intermediate of as a white solid(1.172 g, 95%): mass spectrum (ion spray) m/z=247.9 (M+1); ¹H NMR(CDCl₃, ppm): 8.37 (s, 1H), 7.72 (m, 2H), 7.44 (m, 4H), 6.31 (d, 1H),4.36 (s, br, 2H).

Preparation 46 N-(6-Amino-pyridin-2-yl)-2-bromobenzamide

Using a method similar to Preparation 44, using 2-bromobenzoyl chloride(1.097 g, 5.0 mmol) gives the title intermediate as a white solid (1.445g, 99%): mass spectrum (ion spray): m/z=291.9 (M+1); ¹H NMR (CDCl₃,ppm): 8.27 (s, br, 1H), 7.65 (m, 4H), 7.34 (m, 2H), 6.29 (d, 1H), 4.36(s, br, 2H).

Preparation 47 Cyclohexanecarboxylic acid (6-aminopyridin-2-yl)amide

Using a method similar to Preparation 44, using cyclohexanecarbonylchloride (733 mg, 5.0 mmol) gives the title intermediate as a whitesolid (1.137 g, 100%): mass spectrum (ion spray): m/z=242.0 (M+Na); ¹HNMR (CDCl₃, ppm): 7.97 (s, 1H), 7.56 (d, 1H), 7.43 (dd, 1H), 6.23 (dd,1H), 4.40 (s, br, 2H), 2.18 (m, 1H), 1.81 (m, 4H), 1.66 (1H), 1.46 (2H),1.20 (m, 3H).

Preparation 48 N-(6-Aminopyridin-2-yl)-2-chloro-6-fluorobenzamide

Dissolve 2,6-diaminopyridine (1.3 g, 12 mmol) in dioxane (30 mL). Add2-chloro-6-fluorobenzoyl chloride (768 mg, 4 mmol). Stir under nitrogen(40° C., 64 hr.). Transfer the reaction mixture into ethyl acetate (150mL). Wash with saturated sodium bicarbonate solution (80 mL). Dry overanhydrous sodium sulfate. Remove the solvent under reduced pressure andclean by chromatography (silica gel, 10% ethyl acetate/hexanes) to givethe title intermediate (820 mg, 78% yield): mass spectrum (ion spray):m/z=266.0 (M+1).

Preparation 49 N-(6-Aminopyridin-2-yl)-3-chloro-2,6-difluorobenzamide

Using a method similar to Preparation 48, using3-chloro-2,6-difluorobenzoyl chloride (840 mg, 4 mmol) gives the titleintermediate (761 mg, 67% yield): mass spectrum (ion spray): m/z=284.0(M+1).

Preparation 50 N-(6-Aminopyridin-2-yl)-2,6-difluoro-3-methylbenzamide

Using a method similar to Preparation 48, using2,6-difluoro-3-methylbenzoyl

chloride (760 mg, 4 mmol) gives the title intermediate (669 mg, 64%yield): mass spectrum (ion spray): m/z=264.1 (M+1).

Preparation 51 N-(6-Aminopyridin-2-yl)-2,4-difluorobenzamide

Using a method similar to Preparation 48, using 2,4-difluorobenzoylchloride (704 mg, 4 mmol, stir at 25° C. for 16 hr.) gives the titleintermediate (625 mg, 63% yield): mass spectrum (ion spray): m/z=250.0(M+1).

Preparation 52 N-(6-Aminopyridin-2-yl)-2,6-dichlorobenzamide

Using a method similar to Preparation 48, using 2,6-diaminopyridine (2.6g, 24 mmol), dioxane (75 mL), and 2,6-dichlorobenzoyl chloride (1.68 g,8 mmol) (stir at 25° C. for 16 hr.) gives the title intermediate (1.5 g,66% yield): mass spectrum (ion spray): m/z=282.0 (M+1)

Preparation 53 N-(6-Aminopyridin-2-yl)-2,6-difluorobenzamide

Using a method similar to Preparation 48, using 2,6-diaminopyridine (2.6g, 24 mmol), dioxane (75 mL), and 2,6-difluorobenzoyl chloride (1.4 g, 8mmol) (stir at 25° C. for 16 hr.), gives the title intermediate (1.5 g,75% yield): mass spectrum (ion spray): m/z=250.1 (M+1).

Preparation 54 N-(6-Aminopyridin-2-yl)-2,4-dichlorobenzamide

Using a method similar to Preparation 48, using 2,4-dichlorobenzoylchloride (838 mg, 4 mmol) (stir at 0-25° C. for 16 hr.), gives the titleintermediate (621 mg, 56% yield): mass spectrum (ion spray): m/z=282.0(M+1).

Preparation 55 N-(6-Aminopyridin-2-yl)-2,4,6-trichlorobenzamide

Using a method similar to Preparation 48, using 2,6-diaminopyridine (2.6g, 12 mmol), dioxane (80 mL), and 2,4,6-trichlorobenzoyl chloride (1.95g, 8 mmol) (stir at 0-25° C. for 16 hr.) gives the title intermediate(1.0 g, 39% yield): mass spectrum (ion spray): m/z=316.0 (M+1).

EXAMPLES Example 12-Chloro-4-fluoro-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamidedihydrochloride

Combine 2-chloro-4-fluoro-N-(3-aminophenyl)benzamide (Preparation 1, 200mg, 0.756 mmol), 1-methylpiperidin-4-one (0.093 mL, 0.756 mmol), sodiumtriacetoxyborohydride (208 mg, 0.982 mmol), acetic acid (0.043 mL, 0.756mmol) and dichloromethane (8 mL). Stir at room temperature overnight.Dilute with dichloromethane (5 mL) and wash twice with sodium hydroxide(10 mL 1N aq.). Combine the organic layers and wash with saturatedaqueous NaCl (10 mL). Dry over magnesium sulfate, filter under reducedpressure and concentrate to dryness. Purify by flash chromatography on aBiotage® silica cartridge eluting with a 20/1 mixture of dichloromethaneand 2N ammonia in methanol to give the free base of the title compound(239 mg, 87%). Dissolve the residue in diethyl ether and treat withethereal hydrogen chloride. Triturate the resulting gum with ether togive the title compound as a white solid (31 mg): mp 180° C.; massspectrum (free base, ion spray): m/z=362.1 (M+1), ¹H NMR (free base,CDCl₃): 7.80-7.75 (m, 2H), 7.23 (bs, 1H), 7.19 (dd, J=2.4 Hz, 8.3 Hz,1H), 7.13 (t, J=8.2 Hz, 1H), 7.08 (dd, J=2.4 Hz, 8.3 Hz, 1H), 6.67 (d,J=7.8 Hz, 1H), 6.41 (dd, J=2.0 Hz, 8.3 Hz, 1H), 3.68 (bd, J=7.9 Hz, 1H),3.36 (bs, 1H), 2.92-2.81 (bm, 2H), 2.35 (s, 3H), 2.82-2.17 (bm, 2H),2.10 (bd, J=13.0 Hz, 2H), 1.64-1.51 (bm, 2H). Analysis calc'd forC₁₉H₂₃Cl₃FN₃O: C, 51.95; H, 5.39; N, 9.57. Found: C, 52.03; H, 5.46; N,9.17.

Alternatively, to a solution of1-methyl-4-(3-aminophenylamino)piperidine (92 g, 17 mmol) andtriethylamine (156 mL, 39 mmol) in dry THF (1 L), add dropwise2-chloro-4-fluorobenzoyl chloride (3.6 g, 18.6 mmol), under nitrogen,over 1 hr., keeping the T_(mass) between 20° C. and 26° C. Agitate thesuspension at room temperature for 1 hr. Quench the reaction mixturewith water (100 mL) and 30% NaOH (40 mL) to obtain a biphasic solution(pH˜8-9). Extract with methyl t-butyl ether (500 mL), wash the organiclayer with water (100 mL), dry over MgSO₄, and concentrate under reducedpressure to obtain2-Chloro-4-fluoro-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamide asan amorphous solid. Suspend the solid with methyl t-butyl ether (400 mL)and warm the mixture under reflux for 2 hr. Cool the mixture to roomtemperature, add cyclohexane (100 mL) and methyl t-butyl ether (250 mL).Filter the resulting crystals, rinse with methyl t-butyl ether (160 mL)and dry under reduced pressure at 50° C. overnight to obtain2-Chloro-4-fluoro-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamide asa white powder (123 g, 76% yield).

Example 1A2-Chloro-4-fluoro-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamidefumarate salt

Fumaric acid (170 mg; 1.46 mmol) is added to a suspension of2-Chloro-4-fluoro-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamide(free base of Example 1, 500 mg, 1.38 mmol) in isopropanol (5 mL) atroom temperature. The suspension is heated under reflux for 1 hr.,cooled down to room temperature and post-agitated for 2 hr. The crystalsare filtered, washed with isopropanol (2×0.5 mL) and dried under reducedpressure at 40° C. to give a white solid (665 mg, 100% yield). Thesecrystals (100 mg; 0.21 mmol) are resuspended in water (1 mL) and stirredat room temperature. After 5 min. of stirring, the suspension becomes anorange homogeneous solution (after about 5 min) and then fine crystalsappear (after about 10 min). The mixture is post-agitated overnight. Thesuspension is then filtered, the solid washed with water (0.1 mL) anddried under reduced pressure to give the title compound as a pure whitesolid (76 mg, 76% yield).

Example 22-Chloro-4-fluoro-N-(3-(N-cyclopropylcarbonyl-N-(1-methylpiperidin-4-yl)amino)phenyl)benzamidehydrochloride

Combine2-chloro-4-fluoro-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamidedihydrochloride (Example 1, 48 mg, 0.134 mmol), dioxane (1 mL) andcyclopropylcarbonyl chloride (0.013 mL, 0.148 mmol). Shake and heat(106° C.) in a J-Kem® Reaction Block for 2 hr. Load onto a SCX column(Varian) and elute with 2 M ammonia methanol to give the free base ofthe title compound (54 mg, 93%). Following a salt formation methodsimilar to that described in Example 1 gives the title compound as awhite solid (47 mg): mp 133-6° C.; mass spectrum (freebase, ion spray):m/z=430.1 (M+1), ¹H NMR (freebase, CDCl₃): 8.31 (bs, N—H), 7.76 (dd,J=6.0 Hz, 8.6 Hz, 1H), 7.61-7.56 (m, 2H), 7.38 (t, J=8.0 Hz, 1H), 7.19(dd, J=2.4 Hz, 8.3 Hz, 1H), 7.09 (td, J=2.4 Hz, 8.2 Hz, 1H), 6.96 (d,J=8.2 Hz, 1H), 4.62-4.53 (m, 1H), 2.80 (bd, J=11.5 Hz, 2H), 2.20 (s,3H), 2.05 (td, J=2.2 Hz, 12.1 Hz, 2H), 1.83-1.69 (bm, 2H), 1.59-1.37(bm, 2H), 1.21-1.13 (m, 1H), 0.99-0.89 (bm, 2H), 0.56 (bd, J=7.4 Hz,2H). Analysis calc'd for C₂₃H₂₆Cl₂FN₃O₂.0.8H₂O: C, 57.46; H, 5.79; N,8.74. Found: C, 57.16; H, 5.73; N, 8.70.

Example 32-Chloro-4-fluoro-N-(3-(N-cyclobutanecarbonyl-N-(1-methylpiperidin-4-yl))amino)phenyl)benzamidehydrochloride

Using a method similar to Example 2, using cyclobutylcarbonyl chloride(0.017 mL, 0.148 mmol) gives the title compound as a white solid(freebase, 46 mg, 78%; hydrochloride, 30 mg): mass spectrum (freebase,ion spray): m/z=444.2 (M+1), ¹H NMR (freebase, CDCl₃): 8.29 (bs, N—H),7.77 (dd, J=6.0 Hz, 8.8 Hz, 1H), 7.54 (d, J=8.2 Hz, 1H), 7.50-7.48 (bs,1H), 7.34. (t, J=8.0 Hz, 1H), 7.19 (dd, J=2.4 Hz, 8.5 Hz, 1H), 7.09 (td,J=2.3 Hz, 8.2 Hz, 1H), 4.56 (tt, J=4.2 Hz, 12.1 Hz, 1H), 2.89-2.76 (m,3H), 2.32-2.18 (m, 5H), 2.06 (td, J=2.1 Hz, 12.1 Hz, 2H), 1.82-1.64 (bm,6H), 1.54-1.32 (bm, 2H). Analysis calculated for C₂₄H₂₈Cl₂FN₃O₂.1.0H₂O:C, 57.83; H, 6.07; N, 8.43. Found: C, 57.77; H, 5.97; N, 8.36.

Example 42-Chloro-6-fluoro-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamidedihydrochloride

Using a method similar to Example 1, using2-chloro-6-fluoro-N-(3-aminophenyl)benzamide (Preparation 2, 300 mg,1.133 mmol) gives the title compound as a white solid (free base 358 mg,87%; dihydrochloride 415 mg): mp 192-4° C.; mass spectrum (freebase, ionspray): m/z=362.0 (M+1), ¹H NMR (freebase, CDCl₃): 7.41 (bs, N—H),7.38-7.32 (m, 1H), 7.24 (bs, 1H), 7.13 (t, J=8.2 Hz, 1H), 7.08 (td,J=0.9 Hz, 8.5 Hz, 1H), 6.66 (dd, J=2.0 Hz, 8.0 Hz, 1H), 6.41 (dd, J=2.1Hz, 8.0 Hz, 1H), 3.69 (bd, J=7.9 Hz, 1H), 3.35 (bs, N—H), 2.88-2.80 (bm,2H), 2.33 (s, 3H), 2.19 (bt, J=11.2 Hz, 2H), 2.12-2.05 (bm, 2H),1.61-1.50 (bm, 2H). Analysis calc'd for C₁₉H₂₃Cl₃FN₃O: C, 52.49; H,5.33; N, 9.66. Found: C, 52.24; H, 5.43; N, 9.27.

Example 52,6-Difluoro-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamidedihydrochloride

Using a method similar to Example 1, using2,6-difluoro-N-(3-aminophenyl)benzamide (Preparation 3, 300 mg, 1.208mmol) gives the title compound as a white solid (freebase 355 mg, 85%;dihydrochloride 411 mg): mp 198° C. (dec); mass spectrum (freebase, ionspray): m/z=346.0 (M+1), ¹H NMR (freebase, CDCl₃): 7.55 (bs, N—H),7.45-7.36 (m, 1H), 7.24 (t, J=1.9 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.99(t, J=8.1 Hz, 2H), 6.66 (dd, J=1.4 Hz, 7.8 Hz, 1H), 6.40 (dd, J=2.0 Hz,8.0 Hz, 1H), 3.67 (bd, J=8.1 Hz, 1H), 3.34 (bs, N—H), 2.83 (bd, J=11.0Hz, 2H), 2.32 (s, 3H), 2.18 (bt, J=11.6 Hz, 2H), 2.08 (bd, J=12.7 Hz,2H), 1.59-1.48 (m, 2H). Analysis calc'd for C₁₉H₂₃Cl₂F₂N₃O: C, 54.55; H,5.54; N, 10.04. Found: C, 54.78; H, 5.69; N, 9.78.

Example 62,4-Difluoro-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamidedihydrochloride

Using a method similar to Example 1, using2,4-difluoro-N-(3-aminophenyl)benzamide (Preparation 4, 307 mg, 1.236mmol) gives the title compound as a white solid (freebase 394 mg, 92%;dihydrochloride 394 mg): mp 262° C. (dec); mass spectrum (freebase, ionspray): m/z=346.0 (M+1), ¹H NMR (freebase, CDCl₃): 8.20-8.02 (m, 2H),7.14 (t, J=1.9 Hz, 1H), 7.05 (t, J=8.0 Hz, 1H), 7.00-6.93 (m, 1H),6.92-6.80 (m, 1H), 6.63 (dd, J=1.3 Hz, 7.9 Hz, 1H), 6.33 (dd, J=1.9 Hz,7.9 Hz, 1H), 3.58 (bd, J=8.1 Hz, 1H), 3.27 (bs, N—H), 2.73 (bd, J=11.8Hz, 2H), 2.22 (s, 3H), 2.07 (bt, J=11.1 Hz, 2H), 2.01 (bd, J=12.9 Hz,2H), 1.50-1.35 (m, 2H).

Example 72,4,6-Trifluoro-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamidedihydrochloride

Using a method similar to Example 1, using2,4,6-trifluoro-N-(3-aminophenyl)benzamide (Preparation 5, 290 mg, 1.089mmol) gives the title compound as a white solid (freebase 355 mg, 90%;dihydrochloride 355 mg): mp 257° C. (dec); mass spectrum (freebase, ionspray): m/z=364.0 (M+1), ¹H NMR (freebase, CDCl₃): 7.43 (bs, N—H), 7.13(t, J=2.0 Hz, 1H), 7.05 (t, J=8.0 Hz, 1H), 6.69 (t, J=8.2 Hz, 2H), 6.57(dd, J=1.4 Hz, 7.8 Hz, 1H), 6.33 (dd, J=1.9 Hz, 8.1 Hz, 1H), 3.59 (bd,J=8.0 Hz, 1H), 3.25 (bs, N—H), 2.72 (bd, J=11.8 Hz, 2H), 2.22 (s, 3H),2.06 (bt, J=11.2 Hz, 2H), 2.00 (bd, J=11.7 Hz, 2H), 1.50-1.35 (m, 2H).

Example 8 2-Bromo-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamidedihydrochloride

Using a method similar to Example 1, using2-bromo-N-(3-aminophenyl)benzamide (Preparation 6, 304 mg, 1.044 mmol)gives the title compound as a white solid (free base 377 mg, 93%;dihydrochloride 395 mg): mp 192-3° C.; mass spectrum (free base, ionspray): m/z=388.1 (M+1), ¹H NMR (free base, CDCl₃): 7.65-7.60 (m, 2H),7.57 (bs, N—H), 7.40 (td, J=1.1 Hz, 7.5 Hz, 1H), 7.31 (td, J=1.7 Hz, 7.8Hz, 1H), 7.24 (bt, J=2.1 Hz, 1H), 7.13 (t, J=8.0 Hz, 1H), 6.67 (dd,J=1.5 Hz, 7.9 Hz, 1H), 6.40 (dd, J=2.0 Hz, 8.1 Hz, 1H), 3.68 (bd, J=7.9Hz, 1H), 3.38-3.29 (bm, 1H), 2.82 (bd, J=11.2 Hz, 2H), 2.31 (s, 3H),2.17 (bt, J=11.2 Hz, 2H), 2.08 (bd, J=12.9 Hz, 2H), 1.58-1.47 (m, 2H).Analysis calc'd for C₁₉H₂₄BrCl₂N₃O.0.25H₂O: C, 49.00; H, 5.30; N, 9.02.Found: C, 49.11; H, 5.36; N, 8.69.

Example 9 2-Chloro-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamidedihydrochloride

Using a method similar to Example 1, using2-chloro-N-(3-aminophenyl)benzamide (Preparation 7, 300 mg, 1.216 mmol)gives the title compound as a white solid (free base 331 mg, 79%;dihydrochloride 333 mg): mp 206-8° C.; mass spectrum (free base, ionspray): m/z=344.0 (M+1), ¹H NMR (free base, CDCl₃): 7.75 (bs, N—H), 7.73(dd, J=2.0 Hz, 7.3 Hz, 1H), 7.46-7.34 (m, 3H), 7.25 (bt, J=2.1 Hz, 1H),7.13 (t, J=8.1 Hz, 1H), 6.68 (dd, J=1.3 Hz, 7.9 Hz, 1H), 6.40 (dd, J=2.0Hz, 8.2 Hz, 1H), 3.67 (bd, J=7.7 Hz, 1H), 3.39-3.29 (bm, 1H), 2.83 (bd,J=11.0 Hz, 2H), 2.32 (s, 3H), 2.18 (bt, J=11.5 Hz, 2H), 2.09 (bd, J=12.5Hz, 2H), 1.59-1.48 (bm, 2H). Analysis calc'd for C₁₉H₂₄Cl₃N₃O.0.5H₂O: C,53.60; H, 5:92; N, 9.87. Found: C, 53.94; H, 5.91; N, 9.70.

Example 102-Trifluoromethoxy-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamidedihydrochloride

Using a method similar to Example 1, using2-trifluoromethoxy-N-(3-aminophenyl)benzamide (Preparation 8, 300 mg,1.013 mmol) gives the title compound as a white solid (free base 274 mg,69%; dihydrochloride 325 mg): mp 159-62° C.; mass spectrum (free base,ion spray): m/z=394.2 (M+1), ¹H NMR (free base, CDCl₃): 8.18 (bs, N—H),8.07 (d, J=7.5 Hz, 1H), 7.55 (t, J=7.5 Hz, 1H), 7.45 (t, J=7.5 Hz, 1H),7.34 (d, J=8.0 Hz, 1H), 7.21 (bs, 1H), 7.13 (t, J=8.0 Hz, 1H), 6.68 (d,J=7.5 Hz, 1H), 6.41 (d, J=7.5 Hz, 1H), 3.67 (bd, J=7.1 Hz, 1H),3.38-3.28 (bm, 1H), 2.81 (bd, J=9.5 Hz, 2H), 2.30 (s, 3H), 2.22-2.04(bm, 4H), 1.58-1.46 (bm, 2H).

Example 112,6-Difluoro-N-(3-(N-methyl-N-(1-methylpiperidin-4-yl)amino)phenyl)benzamidedihydrochloride

Combine 1-methyl-4-(N-(3-aminophenyl)-N-methylamino)piperidine(Preparation 11, 101 mg, 0.307 mmol), dichloromethane (6 mL) andpyridine (0.125 mL, 1.535 mmol) at 0° C. Add 2,6-difluorobenzoylchloride (0.048 mL, 0.384 mmol) neat and continue stirring for 1 hr.Dilute with dichloromethane (5 mL) and wash with sodium hydroxide (1Naq., 2×8 mL). Combine the organic layers, dry over magnesium sulphate,filter under reduced pressure and concentrate to dryness. Purify byflash chromatography, eluting with a 20/1 mixture of dichloromethane/(2Nammonia in methanol) to give the free base of the title compound (88 mg,80%). Following a salt formation method similar to that described inExample 1 gives the title compound as a yellow solid (89 mg): massspectrum (free base, ion spray): m/z=360.1 (M+1), ¹H NMR (free base,CDCl₃): 7.56 (bs, 1H), 7.44-7.34 (m, 2H), 7.20 (t, J=8.2 Hz, 1H), 7.00(t, J=8.2 Hz, 2H), 6.78 (d, J=8.0 Hz, 1H), 6.59 (dd, J=2.2 Hz, 8.2 Hz,1H), 3.71-3.63 (bm, 1H), 3.14-3.04 (bm, 2H), 2.82 (s, 3H), 2.41 (bs,3H), 2.11-1.97 (bm, 2H), 1.79 (bd, J=13 Hz, 2H).

Example 122-Chloro-4-fluoro-N-(3-(N-methyl-N-(1-methylpiperidin-4-yl)amino)phenyl)benzamidedihydrochloride

Using a method similar to Example 11, using 2-chloro-4-fluorobenzoylchloride (0.049 mL, 0.384 mmol) gives the title compound (free base 102mg, 89%; dihydrochloride 67 mg, white solid): mp 172° C.; mass spectrum(free base, ion spray): m/z=376.1 (M+1), ¹H NMR (free base, CDCl₃):7.80-7.76 (m, 2H), 7.30 (bs, N—H), 7.22-7.18 (m, 2H), 7.09 (td, J=2.4Hz, 8.1 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 6.60 (dd, J=2.1 Hz, 8.4 Hz,1H), 3.68-3.58 (m, 1H), 3.03 (bd, J=11.0 Hz, 2H), 2.82 (s, 3H), 2.36 (s,3H), 2.23-2.15 (bm, 2H), 2.01-1.89 (bm, 2H), 1.76 (bd, J=12.0 Hz, 2H).Analysis calc'd for C₂₀H₂₅Cl₃FN₃O.0.25H₂O: C, 53.53; H, 5.61; N, 9.36.Found: C, 53.19; H, 5.79; N, 9.36.

Example 132,4,6-Trifluoro-N-(3-(N-methyl-N-(1-methylpiperidin-4-yl)amino)phenyl)benzamidedihydrochloride

Load 1-methyl-4-(N-(3-aminophenyl)-N-methylamino)piperidinetrihydrochloride (Preparation 11, 240 mg, 1.094 mmol) in methanol (2 ml)onto a SCX column (2 g cartridge, Varian). Elute with ammonia (2.0 M inmethanol) to obtain the corresponding free base. Concentrate to dryness.Dissolve the resulting brown oil in dioxane (2 mL) and divide thesolution into two aliquots (2×1 mL). Take one of the aliquots and adddioxane (1 mL). Add 2,4,6-trifluoro-benzoyl chloride (0.052 mL, 0.401mmol) neat. Shake and heat at 106.5° C. for 2 hr. Cool to ambienttemperature and load onto a SCX column (1 g cartridge, Varian). Elutewith ammonia (2.0 M in methanol). Purify further by flash chromatographyusing 20/1 mixture of dichloromethane and 2.0 M ammonia in methanol toprovide the free base of the title compound (86 mg, 62%). Following asalt formation method similar to Example 1 gives the title compound as awhite solid (99 mg): mp 199-200° C.; mass spectrum (free base, ionspray): m/z=378.2 (M+1), ¹H NMR (free base, CDCl₃): 7.44 (bs, N—H), 7.31(bs, 1H), 7.19 (t, J=8.3 Hz, 1H), 6.80-6.73 (m, 3H), 6.60 (dd, J=2.2 Hz,8.3 Hz, 1H), 3.64 (tt, J=4.0 Hz, 11.9 Hz, 1H), 3.05 (bd, J=10.8 Hz, 2H),2.81 (s, 3H), 2.38 (s, 3H), 2.28-2.17 (bm, 2H), 2.06-1.92 (bm, 2H), 1.76(bd, J=12.2 Hz, 2H).

Example 142-Chloro-6-fluoro-N-(3-(N-methyl-N-(1-methylpiperidin-4-yl)amino)phenyl)benzamidedihydrochloride

Using a method similar to Example 13, using 2-chloro-6-fluorobenzoylchloride (0.052 mL, 0.401 mmol) gives the title compound as a whitesolid (free base 100 mg, 73%; dihydrochloride 114 mg): mp 214-7° C.;mass spectrum (free base, ion spray): m/z=376.2 (M+1), ¹H NMR (freebase, CDCl₃): 7.44 (bs, N—H), 7.39-7.32 (m, 2H), 7.27-7.24 (m, 1H), 7.21(t, J=8.1 Hz, 1H), 7.09 (t, J=8.5 Hz, 1H), 6.80 (d, J=8.1 Hz, 1H), 6.60(dd, J=2.3 Hz, 8.4 Hz, 1H), 3.72-3.63 (m, 1H), 3.09 (bd, J=10.1 Hz, 2H),2.82 (s, 3H), 2.41 (s, 3H), 2.33-2.22 (bm, 2H), 2.12-1.99 (bm, 2H), 1.79(bd, J=11.9 Hz, 2H). Analysis calculated for C₂₀H₂₅Cl₃FN₃O: C, 53.53; H,5.61; N, 9.36. Found: C, 53.85; H, 5.72; N, 8.99.

Preparation 564-(3-(2-Chloro-4-fluorobenzoylamino)phenylamino)piperidine-1-carboxylicacid t-butyl ester

Using a method similar to Example 1, using1-t-butoxycarbonyl-4-piperidone (158 mg, 0.793 mmol) gives the titlefree base compound (288 mg, 97%) as an off-white foam: mass spectrum(ion spray): m/z=446.2 (M−1); ¹H NMR (CDCl₃): 7.81 (bs, N—H), 7.76 (dd,J=6.1 Hz, 8.4 Hz, 1H), 7.27 (bs, 1H), 7.19 (dd, J=2.3 Hz, 8.4 Hz, 1H),7.15 (t, J=8.0 Hz, 1H), 7.09 (td, J=2.3 Hz, 8.2 Hz, 1H), 6.72 (bd, J=7.7Hz, 1H), 6.45 (bd, J=8.0 Hz, 1H), 4.09-3.99 (bm, 1H), 3.50-3.41 (bm,1H), 2.92 (bt, J=11.7 Hz, 2H), 2.09-2.01 (bm, 2H), 1.46 (s, 9H),1.71-1.54 (bm, 2H), 1.39-1.33 (bm, 2H).

Example 15 2-Chloro-4-fluoro-N-(3-(piperidin-4-ylamino)phenyl)benzamidedihydrochloride

Combine acetyl chloride (5 ml) and dried methanol (10 ml) at 0° C. undera nitrogen atmosphere. Stir for 1 hr. at 0° C. Add a solution of4-(3-(2-Chloro-4-fluorobenzoylamino) phenylamino)piperidine-1-carboxylicacid t-butyl ester (Preparation 56, 72 mg, 0.161 mmol) in methanol (2mL). Stir overnight. Concentrate under reduced pressure. Triturate withdiethyl ether (1 mL) to provide a pale yellow foam of the titlecompound: mp 255-7° C.; mass spectrum (ion spray): m/z=348.2 (M+1).Analysis calc'd for C₁₈H₂₁Cl₃FN₃O.1.0H₂O: C, 49.28; H, 5.28; N, 9.58.Found: C, 49.15; H, 4.96; N, 9.56.

Example 162-Chloro-N-(3-(N-methyl-N-(1-methylpiperidin-4-yl)amino)phenyl)benzamidedihydrochloride

Combine 2-chloro-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamidedihydrochloride (Example 9, 100 mg, 0.240 mmol), methanol (3 mL) andformaldehyde (37% aq., 0.195 mL, 2.39 mmol). Stir at room temperaturefor 45 min. Cool to 0° C. Add acetic acid (0.412 mL, 7.20 mmol) andsodium cyanoborohydride (26 mg, 0.420 mmol). Stir at room temperatureovernight. Concentrate to dryness. Dissolve the residue in a 2/1 mixtureof ethyl acetate and hexanes (8 mL) and wash with sodium hydroxide (1Naq., 2×6 mL). Separate the organic layer and dry over magnesium sulfate.Filter and concentrate under reduced pressure. Purify through flashchromatography eluting with a 20/1 mixture of dichloromethane and 2Mammonia in methanol to provide the free base of the title compound (69mg, 80%). Following a salt formation method similar to Example 1 givesthe title compound as a white solid (83 mg, white solid): mass spectrum(free base, ion spray): m/z=358.2 (M+1), ¹H NMR (free base, CDCl₃): 7.97(bs, N—H), 7.66 (dd, J=1.7 Hz, 7.5 Hz, 1H), 7.42-7.27 (m, 4H), 7.17 (t,J=8.2 Hz, 1H), 6.82 (dd, J=1.5 Hz, 8.2 Hz, 1H), 6.57 (dd, J=2.3 Hz, 8.4Hz, 1H), 3.59 (tt, J=3.9 Hz, 11.7 Hz, 1H), 2.90 (bd, J=11.7 Hz, 2H),2.78 (s, 3H), 2.26 (s, 3H), 2.05 (td, J=2.3 Hz, 12.0 Hz, 2H), 1.82 (qd,J=3.9 Hz, 12.0 Hz, 2H), 1.70 (bd, J=12.0 Hz, 2H). Analysis calc'd forC₂₀H₂₆Cl₃N₃O 0.25H₂O: C, 55.18; H, 6.14; N, 9.65. Found: C, 55.03; H,6.11; N, 9.26.

Example 172-Bromo-N-(3-(N-methyl-N-(1-methylpiperidin-4-yl)amino)phenyl)benzamidedihydrochloride

Using a method similar to Example 16, using2-bromo-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamidedihydrochloride (Example 8, 100 mg, 0.217 mmol) gives the title compoundas a white solid (free base 62 mg, 71%; dihydrochloride 73 mg): mp196-7° C.; mass spectrum (free base, ion spray): m/z=402.2 (M+1), ¹H NMR(free base, CDCl₃): 7.76 (bd, J=11.3 Hz, N—H), 7.66-7.57 (m, 2H),7.42-7.16 (m, 4H), 6.88-6.81 (m, 1H), 6.63-6 56 (m, 1H), 3.67-3.55 (bm,1H), 2.98-2.89 (bm, 2H), 2.79 (bs, 3H), 2.27 (bs, 3H), 2.13-2.02 (bm,2H), 1.92-1.78 (bm, 2H), 1.77-1.68 (bm, 2H). Analysis calc'd forC₂₀H₂₆BrCl₂N₃O.0.5H₂O: C, 49.61; H, 5.62; N, 8.68. Found: C, 49.84; H,5.85; N, 8.36.

Example 182,4-Difluoro-N-(3-(N-methyl-N-(1-methylpiperidin-4-yl)amino)phenyl)benzamidedihydrochloride

Using a method similar to Example 16, using2,4-difluoro-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamidedihydrochloride (Example 6, 100 mg, 0.239 mmol) gives the title compoundas a white solid (free base 79 mg, 92%; dihydrochloride 94 mg): mp165-8° C.; mass spectrum (free base, ion spray): m/z=360.3 (M+1), ¹H NMR(free base, CDCl₃): 8.28 (bd, J=13.8 Hz, N—H), 8.21-8.12 (bm, 1H),7.29-7.23 (bm, 1H), 7.19 (t, J=8.2 Hz, 1H), 7.06-6.77 (bm, 3H), 6.60 (d,J=7.9 Hz, 1H), 3.65-3.53 (bm, 1H), 2.99-2.88 (bm, 2H), 2.81 (bs, 3H),2.30 (bs, 3H), 2.09 (bt, J=11.0 Hz, 2H), 1.92-1.78 (bm, 2H), 1.73 (bd,J=11.0 Hz, 2H). Analysis calc'd for C₂₀H₂₅Cl₂F₂N₃O: C, 55.56; H, 5.83;N, 9.72. Found: C, 55.62; H, 5.95; N, 9.69.

Preparation 574-(N-(3-(2-Chloro-4-fluorobenzoylamino)phenyl)methylamino)piperidine-1-carboxylicacid t-butyl ester

Using a method similar to Example 16, using4-(3-(2-chloro-4-fluorobenzoylamino)phenylamino)piperidine-1-carboxylicacid t-butyl ester (Preparation 56, 165 mg, 0.368 mmol) gives the titlefree base compound (169 mg, 99%): mass spectrum (ion spray): m/z=462.2(M+1). ¹H NMR (CDCl₃): 8.13 (bs, N—H), 7.67 (dd, J=6.0 Hz, 8.6 Hz, 1H),7.31 (bt, J=2.0 Hz, 1H), 7.18 (t, J=8.2 Hz, 1H), 7.13 (dd, J=2.3 Hz, 8.6Hz, 1H), 7.01 (td, J=2.3 Hz, 8.2 Hz, 1H), 6.83 (bd, J=8.0 Hz, 1H), 6.59(dd, J=2.3 Hz, 8.4 Hz, 1H), 4.24-4.14 (bm, 2H), 3.72 (tt, J=3.8 Hz, 11.5Hz, 1H), 2.76-2.73 (m, 5H), 1.74-1.56 (bm, 4H), 1.45 (s, 9H).

Example 192-Chloro-4-fluoro-N-(3-(N-piperidin-4-yl)methylamino)phenyl)benzamidedihydrochloride

Using a method similar to Example 15, using4-(N-(3-(2-Chloro-4-fluorobenzoylamino)phenyl)methylamino)piperidine-1-carboxylicacid t-butyl ester (Preparation 57, 169 mg, 0.366 mmol) gives the titlecompound as an off-white solid: mass spectrum (ion spray): m/z=362.1(M+1); ¹H NMR (free base, CDCl₃): 7.84 (bs, N—H), 7.68 (dd, J=6.1 Hz,8.6 Hz, 1H), 7.21-7.19 (m, 1H), 7.15-7.09 (m, 2H), 7.00 (td, J=2.3 Hz,8.2 Hz, 1H), 6.75 (bd, J=8.0 Hz, 1H), 6.54 (dd, J=2.1 Hz, 8.4 Hz, 1H),3.68-3.59 (bm, 1H), 3.25-3.08 (bm, 2H), 2.74 (s, 3H), 2.73-2.62 (bm,2H), 1.81-1.60 (bm, 4H). Analysis calc'd for C₁₉H₂₃Cl₃FN₃O.0.1H₂O: C,52.27; H, 5.36; N, 9.63. Found: C, 52.60; H, 5.75; N, 9.29.

Example 202-Chloro-4-fluoro-N-(3-(1-ethylpiperidin-4-ylamino)phenyl)benzamidedihydrochloride

Using a method similar to Example 1, using 1-ethylpiperidin-4-one (0.102mL, 0.756 mmol) gives the title compound as a white solid (143 mg, 50%):mass spectrum (free base, ion spray): m/z=376.1 (M+1); ¹H NMR (freebase, CDCl₃): 7.77 (bs, N—H), 7.76 (dd, J=6.1 Hz, 8.7 Hz, 1H), 7.21 (d,J=2.1 Hz, 1H), 7.18 (dd, J=2.5 Hz, 8.3 Hz, 1H), 7.12 (t, J=8.1 Hz, 1H),7.08 (td, J=2.5 Hz, 8.3 Hz, 1H), 6.67 (bd, J=8.0 Hz, 1H), 6.40 (dd,J=2.0 Hz, 8.1 Hz, 1H), 3.67 (bd, J=8.0 Hz, 1H), 3.39-3.29 (bm, 1H),2.92-2.85 (bm, 2H), 2.42 (q, J=7.2 Hz, 2H), 2.16-2.05 (bm, 4H),1.55-1.44 (bm, 2H), 1.09 (t, J=7.2 Hz, 3H).

Example 212-Chloro-4-fluoro-N-(3-(1-propylpiperidin-4-ylamino)phenyl)benzamidedihydrochloride

Using a method similar to Example 1, using 1-propylpiperidin-4-one(0.114 mL, 0.756 mmol) gives the title compound as a white solid (262mg, 89%): mass spectrum (free base, ion spray): m/z=390.2 (M+1); ¹H NMR(free base, CDCl₃): 7.89 (bs, N—H), 7.71 (dd, J=6.0 Hz, 8.7 Hz, 1H),7.19 (bt, J=2.0 Hz, 1H), 7.16 (dd, J=2.5 Hz, 8.6 Hz, 1H), 7.11 (t, J=8.0Hz, 1H), 7.05 (td, J=2.5 Hz, 8.1 Hz, 1H), 6.68 (bd, J=8.0 Hz, 1H), 6.39(dd, J=2.0 Hz, 8.0 Hz, 1H), 3.67 (bd, J=7.8 Hz, 1H), 3.36-3.26 (bm, 1H),2.86 (bd, J=11.6 Hz, 2H), 2.32-2.27 (m, 2H), 2.14-2.02 (bm, 4H),1.56-1.43 (bm, 4H), 0.89 (t, J=7.4 Hz, 3H).

Example 222-Chloro-4-fluoro-N-(3-(N-(1-propylpiperidin-4-yl)methylamino)phenyl)benzamidedihydrochloride

Using a method similar to Example 16, using2-chloro-4-fluoro-N-(3-(1-propylpiperidin-4-ylamino)phenyl)benzamidedihydrochloride (Example 21, 71 mg, 0.153 mmol) gives the title compoundas a white solid (43 mg, 69%): mass spectrum (free base, ion spray):m/z=404.1 (M+1); ¹H NMR (free base, CDCl₃): 7.87 (bs, N—H), 7.64 (dd,J=6.1 Hz, 8.6 Hz, 1H), 7.20 (s, 1H), 7.14-7.07 (m, 2H), 6.97 (td, J=2.3Hz, 8.2 Hz, 1H), 6.75 (d, J=8.2 Hz, 1H), 6.51 (dd, J=2.1 Hz, 8.6 Hz,1H), 3.54 (tt, J=3.8 Hz, 11.7 Hz, 1H), 2.97 (bd, J=11.4 Hz, 2H), 2.73(s, 3H), 2.27-2.22 (m, 2H), 1.98 (bt, J=11.7 Hz, 2H), 1.80 (bqd, J=3.5Hz, 12.5 Hz, 2H), 1.66 (bd, J=11.7 Hz, 2H), 1.51-1.41 (m, 2H), 0.83 (t,J=7.4 Hz, 3H).

Example 232-Chloro-4-fluoro-N-(3-(N-(1-(2-(1-isopropyl-1H-pyrazol-4-yl)ethyl)piperidin-4-yl)methylamino)phenyl)benzamidedihydrochloride

Combine 1-isopropyl-2-hydroxyethyl-1H-pyrazole (Preparation 10, 2 g,12.9 mmol), and triethylamine (3.6 mL, 25.9 mmol) in 30 mL of THF. Addmethanesulfonyl chloride (1.3 mL, 15.6 mmol) and stir for 36 hr. Dilutewith water and ethyl acetate. Separate and extract the aqueous layerwith CH₂Cl₂ (2 times). Combine organics, dry over MgSO₄, and concentratein vacuo. Take a portion of this crude mixture (55 mg, 0.237 mmol) andcombine with2-Chloro-4-fluoro-N-(3-(N-piperidin-4-yl)methylamino)phenyl)benzamidedihydrochloride (Example 19, 78 mg, 0.179 mmol), potassium carbonate (99mg, 0.716 mmol) and acetonitrile (3 mL). Stir and heat at 80° C.overnight. Cool to room temperature and filter through a silica plug.Concentrate the filtrate. Purify through flash chromatography elutingwith a 20/1 mixture of CH₂Cl₂ and 2.0 M ammonia in methanol. Dissolvethe residue in diethyl ether and treat with ethereal hydrogen chloride.Triturate the resulting gum with ether to give the title compound as anoff-white solid (53 mg, 60%): mass spectrum (free base, ion spray):m/z=498.1 (M+1); ¹H NMR (free base, CDCl₃): 7.79 (bs, N—H), 7.78 (dd,J=6.0 Hz, 8.7 Hz, 1H), 7.35 (s, 1H), 7.29 (bs, 1H), 7.24 (s, 1H),7.23-7.18 (m, 2H), 7.09 (td, J=2.5 Hz, 8.2 Hz, 1H), 6.80 (bd, J=7.8 Hz,1H), 6.61 (dd, J=2.3 Hz, 8.3 Hz, 1H), 4.44 (septet, J=6.4 Hz, 1H),3.69-3.60 (bm, 1H), 3.11 (bd, J=11.0 Hz, 2H), 2.83 (s, 3H), 2 71-2.64(bm, 2H), 2.60-2.55 (bm, 2H), 2.21-2.11 (bm, 2H), 1.94-1.83 (bm, 2H),1.81-1.74 (bm, 2H), 1.48 (d, J=6.4 Hz, 6H).

Example 242-Chloro-4-fluoro-N-(3-(1-methylpiperidin-4-ylamino)-4-fluorophenyl)benzamidehydrochloride

Under an inert atmosphere, stir a mixture of2-chloro-4-fluoro-N-(3-amino-4-fluorophenyl)benzamide (Preparation 14,481 mg, 1.7 mmol), 1-methyl-4-piperidone (384 mg, 0.42 mL, 3.4 mmol),1,2-dichloroethane (15 mL), powdered molecular sieves 4 Å (1 g) for 15min. Add glacial acetic acid (306 mg, 0.3 mL, 5.1 mmol). After 1 hr.,add sodium triacetoxyborohydride (900 mg, 4.25 mmol). Allow the reactionto go overnight. Pour the reaction mixture into ethyl acetate (200 mL),and wash once with aqueous NaOH (2N, 30 mL). Separate the organic layer,dry over anhydrous sodium sulfate, remove the solvent under reducedpressure. Further purify the residue by chromatography on silica gelusing a 4%-6% gradient of (2M NH₃ in methanol) in CH₂Cl₂ to obtain thefree base of the title compound (443 mg, 69% yield). Convert the productto its HCl salt by dissolving it in CH₂Cl₂ and treating with excess 1.0MHCl in diethyl ether. Add more ether to precipitate the title compoundas a white solid: mass spectrum (ion spray): m/z=380.2 (M+1); Analysiscalculated C₁₉H₂₀ClF₂N₃O.HCl.H₂O: C, 52.54; H, 5.34; N, 9.68. Found: C,52.93; H, 5.29; N, 9.65; LY 653915: ¹H NMR δ (methanol-d) 7.72 (dd, 1H),7.60 (m, 1H), 7.37 (dd, 1H), 7.14 (m, 3H), 3.74 (m, 1H), 3.62 (d, 2H),3.30 (dd, 2H), 2.88 (s, 3H), 2.36 (d, 2H), 1.93 (m, 2H)

Example 252,4-Difluoro-N-(3-(1-methylpiperidin-4-ylamino)-4-fluorophenyl)benzamidehydrochloride

Using a procedure similar Example 24 using2,4-difluoro-N-(3-amino-4-fluorophenyl)benzamide (Preparation 16, 452mg, 1.7 mmol), 1-methyl-4-piperidone (384 mg, 0.42 mL, 3.4 mmol),1,2-dichloroethane (15 mL), powdered molecular sieves 4 Å (1 g), glacialacetic acid (306 mg, 0.3 mL, 5.1 mmol), sodium triacetoxyborohydride(900 mg, 4.25 mmol) to obtain the free base of the title compound (434mg, 70% yield) and the title compound: mass spectrum (ion spray):m/z=364.1 (M+1); analysis calculated for C₁₉H₂₀F₃N₃O.HCl.H₂O: C, 54.61;H, 5.55; N, 10.06. Found: C, 54.48; H, 5.36; N, 9.93; ¹H NMR δ(methanol-d₄) 7.79 (m, 1H), 7.63 (d, 1H), 7.11 (m, 4H), 3.74 (m, 1H),3.62 (d, 2H), 3.30 (dd, 2H), 2.88 (s, 3H), 2.36 (d, 2H), 1.93 (m, 2H)

Example 26 3-Methyl-N-(3-(1-methylpiperidin-4-ylamino)phenyl)butyramidehydrochloride

Combine 1-methyl-4-(3-aminophenylamino)piperidine triacetate(Preparation 18, 460 mg, 1.17 mmol) and CH₂Cl₂ (13 mL); stir and cool to0° C. Add isovaleryl chloride (135 μL, 1.05 mmol), and stir at roomtemperature for 18 hr. Load onto a 5 g SCX cartridge (mega bond elut,Varian). Wash resin with methanol, then elute product with 2 M ammoniain methanol. Concentrate in vacuo, and chromatograph on silica gel,eluting with a gradient of 1-15% (2M ammonia in methanol) in CH₂Cl₂.Concentrate in vacuo. Dissolve the purified oil (115 mg, 38% isolatedyield) in methanol, add solid NH₄Cl (21.2 mg, 1 eq) and sonicate thesolution at room temperature for 15 min. Concentrate in vacuo to providethe title compound: mass spectrum (ion spray): m/z=290.2 (M+1); Analcalculated for C₁₇H₂₈ClN₃O.0.1H₂O: Theory: C, 62.31; H, 8.67; N, 12.82.Found: C, 62.32; H, 8.78; N, 12.56.

Example 27 4-Fluoro-N-(3-(1-methyl-piperidin-4-ylamino)phenyl)benzamidehydrochloride

A method similar to Example 26, using 4-fluorobenzoyl chloride, givesthe title compound as a white solid (127 mg): mass spectrum (ion spray):m/z=328.1 (M+1); Anal calc'd for C₁₉H₂₃ClFN₃O.0.1H₂O: Theory: C, 62.41;H, 6.39; N, 11.49. Found: C, 62.13; H, 6.55; N, 11.14.

Example 28Cyclopropane-N-(3-(1-methyl-piperidin-4-ylamino)phenyl)carboxamidehydrochloride

A method similar to Example 26, using cyclopropanecarbonyl chloride,gives the title compound as a white solid (80 mg): mass spectrum (ionspray): m/z=274.1 (M+1); Anal calc'd for C₁₆H₂₄ClN₃O.1.0H₂O: Theory: C,58.62; H, 7.99; N, 12.82. Found: C, 58.47; H, 8.00; N, 12.73.

Example 29 2-Methyl-N-(3-(1-methyl-piperidin-4-ylamino)phenyl)benzamidehydrochloride

A method similar to Example 26, using 2-methylbenzoyl chloride, givesthe title compound as a white solid (32 mg): mass spectrum (ion spray):m/z=324.2 (M+1); ¹H NMR δ (DMSO, ppm) 10.02 (s, 1H), 7.37 (m, 1H), 7.25(m, 4H), 7.02 (t, J=8.1, 16.1 Hz, 1H), 6.82 (d, J=7.7 Hz, 1H), 6.34 (d,J=8.4 Hz, 1H), 5.76 (m, 1H), 3.40 (m, 2H), 3.11 (bs, 2H), 2.71 (s, 3H),2.36 (s, 3H), 2.29 (s, 1H), 2.05 (m, 2H), 1.70 (m, 2H)

Example 30 N-(3-(1-Methyl-piperidin-4-ylamino)phenyl)isonicotinamide

A method similar to Example 26, but not making the HCl salt, usingisonicotinyl chloride, gives the title compound as a yellow oil (30 mg):mass spectrum (ion spray): m/z=310.0 (M+1).

Example 312,6-Dichloro-N-(3-(1-methyl-piperidin-4-ylamino)phenyl)benzamidehydrochloride

A method similar to Example 26, using 2,6-dichlorobenzoyl chloride,gives the title compound as a white solid (174 mg): mass spectrum (ionspray): m/z=378.0 (M+1); ¹H NMR δ (DMSO, ppm) 10.45 (s, 1H), 7.52 (m,2H), 7.22 (m, 2H), 7.05 (t, J=8.1, 16.1 Hz, 1H), 6.76 (d, J=8.1 Hz, 1H),6.38 (d, J=8.1 Hz, 1H), 5.84 (d, J=7.0 Hz, 1H), 3.40 (m, 2H), 3.17 (bs,2H), 2.72 (s, 3H), 2.30 (s, 1H), 2.06 (m, 2H), 1.69 (m, 2H).

Example 32N-(3-(1-Methyl-piperidin-4-ylamino)phenyl)-2-trifluoromethyl-benzamidehydrochloride

A method similar to Example 26, using 2-trifluoromethylbenzoyl chloride,gives the title compound as a white solid (147 mg): mass spectrum (ionspray): m/z=378.1 (M+1); ¹H NMR δ (DMSO, ppm) 10.29 (s, 1H), 7.75 (m,2H), 7.21 (m, 3H), 7.04 (t, J=8.1, 16.1 Hz, 1H), 6.77 (d, J=7.7 Hz, 1H),6.37 (d, J=7.7 Hz, 1H), 5.81 (d, J=7.3 Hz, 1H), 3.40 (m, 2H), 3.10 (bs,2H), 2.72 (s, 3H), 2.30 (s, 1H), 2.06 (m, 2H), 1.71 (m, 2H).

Example 334-Fluoro-N-(3-(1-methyl-piperidin-4-ylamino)phenyl)-2-trifluoromethyl-benzamidehydrochloride

A method similar to Example 26, using 4-fluoro-2-trifluoromethylbenzoylchloride, gives the title compound as a white solid (174 mg): massspectrum (ion spray): m/z=396.1 (M+1); Anal calc'd forC₂₀H₂₂ClF₄N₃O.0.5H₂O: Theory: C, 54.49; H, 5.26; N, 9.53. Found: C,54.88; H, 5.56; N, 9.89.

Example 342,6-Dichloro-(3-(methyl-(1-methyl-piperidin-4-yl)-amino)phenyl)benzamidehydrochloride

Dissolve2,6-dichloro-N-(3-(1-methyl-piperidin-4-ylamino)phenyl)benzamidehydrochloride (Example 31, 168 mg, 0.40 mmol) in 5 mL of methanol. Addan excess of 50% aqueous formaldehyde solution (600 μL), and stir thereaction for 0.5 hr. Adjust the solution to pH=5 by the addition ofacetic acid, add sodium cyanoborohydride (100 mg), and stir the reactionfor an additional 18 hr. Load onto a 5 g SCX cartridge (mega bond elut,Varian). Wash the resin with methanol, then remove the product with 2MNH₃/methanol. Dissolve the resulting oil (153 mg, 98% isolated yield) inmethanol, add NH₄Cl (20.9 mg, 1 eq) as a solid, and sonicate thesolution at room temperature for 15 min. Concentrate in vacuo to providethe title compound: mass spectrum (ion spray): m/z=392.3 (M+1); mp164.2° C.

Example 354-Fluoro-N-(3-(methyl-(1-methyl-piperidin-4-yl)-amino)phenyl)benzamidehydrochloride

A method similar to Example 34, using4-fluoro-N-(3-(1-methyl-piperidin-4-ylamino)phenyl)benzamidehydrochloride (Example 27), gives the title compound as a white solid(102 mg): mass spectrum (ion spray): m/z=342.4 (M+1); mp 76.1° C.

Example 362-Methyl-N-(3-(methyl-(1-methyl-piperidin-4-yl)-amino)phenyl)benzamidehydrochloride

A method similar to Example 34, using2-methyl-N-(3-(1-methyl-piperidin-4-ylamino)phenyl)benzamidehydrochloride (Example 39), gives the title compound as a white solid(25 mg): mass spectrum (ion spray): m/z=338.4 (M+1); mp 82.4° C.

Example 374-Fluoro-N-(3-(methyl-(1-methyl-piperidin-4-yl)-amino)phenyl)-2-trifluoromethyl-benzamidehydrochloride

A method similar to Example 34, using4-fluoro-N-(3-(1-methyl-piperidin-4-ylamino)phenyl)-2-trifluoromethyl-benzamidehydrochloride (Example 33), gives the title compound as a white solid(114 mg): mass spectrum (ion spray): m/z=410.4 (M+1); mp 113. 8° C.

Example 38N-(3-(Methyl-(1-methyl-piperidin-4-yl)-amino)phenyl)-2-trifluoromethyl-benzamidehydrochloride

A method similar to Example 34, usingN-(3-(1-methyl-piperidin-4-ylamino)phenyl)-2-trifluoromethyl-benzamidehydrochloride (Example 32), gives the title compound as a white solid(125 mg): mass spectrum (ion spray): m/z=392.4 (M+1); mp 84.5° C.

Preparation 58(2S,4S)-4-(3-(2-Chloro-4-fluoro-benzoylamino)-phenylamino)-2-methyl-piperidine-1-carboxylicacid tert-butyl ester

Dissolve N-(3-amino-phenyl)-2-chloro-4-fluoro-benzamide (Preparation 1,200 mg, 0.756 mmol) and (2S)-2-methyl-4-oxo-piperidine-1-carboxylic acidtert-butyl ester (161 mg, 0.756 mmol) in tetrahydrofuran (5 mL). Addacetic acid (52 μL, 0.907 mmol) and sodium triacetoxyborohydride (192mg, 0.907 mmol) and stir at room temperature for 18 hr. Heat thereaction to 45° C. for 4 hr. Cool the reaction to room temperature andload onto an SCX column with methanol. Wash the column with methanol,flush with 2M ammonia in methanol, and concentrate in vacuo. Purify bycolumn chromatography (20%-75% ethyl acetate/hexane) to yield 161 mg(46%) of the title compound. Mass spectrum (ion spray): m/z 462.4 (M+1);¹H NMR: δ (CDCl₃, ppm) 7.76 (m, 2H), 7.20 (m, 1H), 7.15 (m, 1H), 7.10(m, 1H), 6.70 (d, J=7.6 Hz, 1H), 6.40 (d, J=8.4 Hz, 1H), 4.20 (m, 1H),3.82 (m, 2H), 3.67 (bs, 1H), 3.20 (m, 1H), 2.00 (m, 2H), 1.65 (m, 2H),1.47 (s, 9H), 1.27, (m, 4H).

Example 392-Chloro-4-fluoro-N-((2S,4S)-3-(2-methyl-piperidin-4-ylamino)-phenyl)-benzamidehydrochloride

Dissolve(2S,4S)-4-(3-(2-chloro-4-fluoro-benzoylamino)-phenylamino)-2-methyl-piperidine-1-carboxylicacid tert-butyl ester (Preparation 58, 137 mg, 0.296 mmol) in toluene(10 mL). Add p-toluenesulfonyl chloride (152 mg, 0.798 mmol) and heat to100° C. for 2 hr. Cool to room temperature and load onto an SCX columnwith methanol. Wash the column with methanol, flush with 2M ammonia inmethanol, and concentrate in vacuo. Purify by column chromatography(0%-15% 2 M NH₃ in methanol/CH₂Cl₂) to yield an oil. Make thehydrochloride salt by sonication with one equivalent of ammoniumchloride dissolved in methanol to yield 75 mg (64%) of the titlecompound. Mass spectrum (ion spray): m/z=362.1 (M+1), ¹H NMR δ (D₂O/DCl,ppm) 7.78 (s, 1H), 7.49 (m, 3H), 7.21 (t, J=9 Hz, 18 Hz, 2H), 7.07 (t,J=9.0 Hz, 18.0 Hz, 1H), 3.83 (m, 1H), 3.45 (m, 1H), 3.20 (m, 1H), 2.95(m, 1H), 2.18 (m, 2H), 1.80 (m, 1H), 1.65 (m, 1H), 1.20 (d, J=6.6 Hz,3H); mp 202° C. (dec.).

Example 402-Chloro-N-((2S,4S)-3-(1,2-dimethyl-piperidin-4-ylamino)-phenyl)-4-fluoro-benzamidehydrochloride

Dissolve2-chloro-4-fluoro-N-((2S,4S)-3-(2-methyl-piperidin-4-ylamino)-phenyl)-benzamidehydrochloride (Example 39, 50 mg, 0.125 mmol) in methanol (5 mL). Addacetic acid (22 μL, 0.375 mmol) followed by sodium cyanoborohydride(11.8 mg, 0.188 mmol). Cool to 0° C. and add 37% formaldehyde (11.2 μL,0.138 mmol). Warm to room temperature and stir for 18 hr. Add aqueoussaturated sodium bicarbonate and dichloromethane. Separate organic layerand extract aqueous with dichloromethane (2×25 mL). Combine organicextracts, dry (MgSO₄), filter, and concentrate in vacuo. Purify bycolumn chromatography (0%-10% 2M NH₃ in methanol/CH₂Cl₂) to yield anoil. Make the hydrochloride salt by sonication with one equivalent ofammonium chloride dissolved in methanol to yield 28 mg (54%) of thetitle compound: mass spectrum (ion spray): m/z 376.2 (M+1); ¹H NMR δ(D₂O/DCl, ppm) 7.71 (s, 1H), 7.90 (m, 3H), 7.16 (m, 2H), 7.02 (m, 1H),3.82 (m, 1H), 3.48 (m, 1H), 3.12 (m, 1H), 2.98 (m, 1H), 2.68 (s, 3H),2.15 (m, 2H), 1.83 (s, 1H), 1.72 (m, 1H), 1.20 (d, J=6.3 Hz, 3H); mp91-4° C.

Preparation 59(2R,4R)-4-(3-(2-Chloro-4-fluoro-benzoylamino)-phenylamino)-2-methyl-piperidine-1-carboxylicacid tert-butyl ester

Dissolve N-(3-amino-phenyl)-2-chloro-4-fluoro-benzamide (Preparation 1,200 mg, 0.756 mmol) and (2R)-2-methyl-4-oxo-piperidine-1-carboxylic acidtert-butyl ester (161 mg, 0.756 mmol) in tetrahydrofuran (5 mL). Addacetic acid (52 μl, 0.907 mmol) and sodium triacetoxyborohydride (192mg, 0.907 mmol) and stir at room temperature for 18 hr. Heat thereaction to 45° C. for 4 hr. Cool the reaction to room temperature andload onto an SCX column with methanol. Wash the column with methanol,flush with 2M ammonia in methanol, and concentrate in vacuo. Purify bycolumn chromatography (20%-75% ethyl acetate/hexane) to yield 80 mg(23%) of the title compound: mass spectrum (ion spray): m/z=462.4 (M+1);¹H NMR: δ (CDCl₃, ppm) 7.76 (m, 2H), 7.20 (m, 1H), 7.15 (m, 1H), 7.10(m, 1H), 6.70 (d, J=7.6 Hz, 1H), 6.40 (d, J=8.4 Hz, 1H), 4.20 (m, 1H),3.82 (m, 2H), 3.67 (bs, 1H), 3.20 (m, 1H), 2.00 (m, 2H), 1.65 (m, 2H),1.47 (s, 9H), 1.27, (m, 4H).

Example 412-Chloro-4-fluoro-N-((2R,4R)-3-(2-methyl-piperidin-4-ylamino)-phenyl)-benzamidehydrochloride

Dissolve(2R,4R)-4-(3-(2-chloro-4-fluoro-benzoylamino)-phenylamino)-2-methyl-piperidine-1-carboxylicacid tert-butyl ester (Preparation 59, 119 mg, 0.258 mmol) in toluene (5mL). Add p-toluenesulfonyl chloride (152 mg, 0.798 mmol) and heat to100° C. for 3 hr. Cool to room temperature and load onto an SCX columnwith methanol. Wash the column with methanol, flush with 2M ammonia inmethanol, and concentrate in vacuo. Purify by column chromatography(0%-10% 2M NH₃ in methanol/CH₂Cl₂) to yield an oil. Make thehydrochloride salt by sonication with one equivalent of ammoniumchloride dissolved in methanol to yield 40 mg (39%) of the titlecompound: mass spectrum (ion spray): m/z=362.1 (M+1); ¹H NMR δ (D₂O/DCl,ppm) 7.78 (s, 1H), 7.49 (m, 3H), 7.21 (t, J=9.0 Hz, 18.0 Hz, 2H), 7.07(t, J=9.0 Hz, 18.0 Hz, 1H), 3.83 (m, 1H), 3.45 (m, 1H), 3.20 (m, 1H),2.95 (m, 1H), 2.18 (m, 2H), 1.80 (m, 1H), 1.65 (m, 1H), 1.20 (d, J=6.6Hz, 3H); mp 182-5° C.

Example 422-Chloro-N-((2R,4R)-3-(1,2-dimethyl-piperidin-4-ylamino)-phenyl)-4-fluoro-benzamidehydrochloride

Dissolve2-chloro-4-fluoro-N-((2R,4R)-3-(2-methyl-piperidin-4-ylamino)-phenyl)-benzamidehydrochloride (Example 41, 30 mg, 0.075 mmol) in methanol (5 mL). Addacetic acid (13 μL, 0.225 mmol) followed by sodium cyanoborohydride (7.1mg, 0.113 mmol). Cool to 0° C. and add 37% formaldehyde (6.7 μL, 0.083mmol). Warm to room temperature and stir for 18 hr. Add aqueoussaturated sodium bicarbonate and dichloromethane. Separate organic layerand extract aqueous with dichloromethane (2×25 mL). Combine organicextracts, dry (MgSO₄), filter, and concentrate in vacuo. Purify bycolumn chromatography (0%-10% 2M NH₃ in methanol/CH₂Cl₂) to yield anoil. Make the hydrochloride salt by sonication with one equivalent ofammonium chloride dissolved in methanol to yield 21 mg (68%) of thetitle compound. Mass spectrum (ion spray): m/z=376.4 (M+1); mp 159-62°C.

Example 432-Chloro-4-fluoro-N-(2-fluoro-3-(1-methyl-piperidinylamino)-phenyl)-benzamide

Mix 2-fluoro-N-(1-methyl-piperidin-4-yl)-benzene-1,3-diamine(Preparation 20) (0.08 g) and 2-chloro-4-fluorobenzoyl chloride (83 mg)in 1,4-dioxane (5 mL) and heat at reflux for 2 hr. Partition thereaction mixture between ethyl acetate and saturated aqueous NaCl, dryover anhydrous sodium sulfate, evaporate and purify on a silica gelcolumn (10 g) (dichloromethane-2M NH₃ in methanol, gradient) to give0.106 g of the title compound (78% yield): mass spectrum (ion spray):m/z=380 (M+1); ¹H NMR (CDCl₃): 8.19 (br s, 1H), 7.83 (dd, 1H), 7.66 (dd,1H), 7.19 (dd, 1H), 7.09 (ddd, 1H), 7.00 (dd, 1H), 6.52 (ddd, 1H), 3.76(br d, 1H), 3.29 (m, 1H), 2.81 (br d, 2H), 2.29 (s, 3H), 2.13 (m, 2H),2.05 (m, 2H), 1.52 (m, 2H).

Dissolve the benzamide in methanol, add 0.28 mL of 1 N HCl in ether andevaporate to give its mono-hydrochloric acid salt.

Example 442-Chloro-4-fluoro-N-(2-fluoro-3-(methyl-(1-methyl-piperidin-4-yl)-amino)-phenyl)-benzamide

Heat 2-fluoro-N-methyl-N-(1-methyl-piperidin-4-yl)-benzene-1,3-diamine(Preparation 22, 44 mg) with 2-chloro-4-fluorobenzoyl chloride (40 mg)in 1,4-dioxane (5 mL) at reflux for 2 hr. Dilute the reaction mixturewith methanol (5 mL) and load on a SCX column (10 g). After wash withmethanol, elute the product with 2 M NH₃ in methanol, evaporate to give73 mg of the title compound: mass spectrum (electric spray) m/z=394(M+1); ¹H NMR (CDCl₃): 8.29 (br d, 1H), 7.94 (t, 1H), 7.81 (dd, 1H),7.18 (dd, 1H), 7.05 (m, 2H), 6.77 (ddd, 1H), 3.15 (m, 1H), 2.72 (s, 3H),2.26 (s, 3H), 1.96 (m, 2H), 1.83 (m, 2H), 1.70 (m, 2H).

The benzamide is dissolved in methylene chloride and 0.185 mL of 1N HClin ether is added and evaporated, dried in vacuum to give itsmonohydrochloric acid salt.

Example 452,4,6-Trifluoro-N-(2-fluoro-3-(methyl-(1-methyl-piperidin-4-yl)-amino)-phenyl)-benzamide

Heat a mixture of2-fluoro-N-methyl-N-(1-methyl-piperidin-4-yl)-benzene-1,3-diamine(Preparation 22, 60 mg) and 2,4,6-trifluorobenzoyl chloride (59 mg) in1,4-dioxane (5 mL) for 2 hr. Dilute the reaction mixture with methanol(5 mL) and load on a SCX column (10 g). After wash with methanol, elutethe product with 2M NH₃ in methanol, evaporate and purify on a silicagel column (4 g, solvent: dichloromethane-2M NH₃ in methanol, gradient)to give 94 mg of the title compound: mass spectrum (electric spray)m/z=396 (M+1); ¹H NMR (CDCl₃): 7.96 (m, 1H), 7.84 (br s, 1H), 7.05 (m,1H), 6.79 (m, 3H), 3.48 (d, 1H), 3.16 (m, 3H), 2.91 (br d, 2H), 2.74 (s,3H), 2.27 (s, 3H), 1.97 (m, 2H), 1.84 (m, 2H), 1.72 (m, 2H).

Dissolve the benzamide in methanol (2 mL), add 1N HCl in ether (0.24mL), evaporate to give its mono-hydrochloric acid salt.

Example 462,4-Difluoro-N-(2-fluoro-3-(methyl-(1-methyl-piperidin-4-yl)-amino)-phenyl)-benzamide

Using a method similar to example 45, using 2,4-difluorobenzoyl chloridegives the title compound: mass spectrum (electric spray) m/z=378 (M+1);¹H NMR (CDCl₃): 8.67 (br d, 1H), 8.21 (m, 1H), 8.00 (m, 1H), 7.04 (m,1H), 6.94 (m, 1H), 6.77 (m, 1H), 3.17 (m, 1H), 2.90 (br d, 2H), 2.75 (s,3H), 2.26 (s, 3H), 1.97 (m, 2H), 1.84 (m, 2H), 1.72 (m, 2H). Using amethod similar to the above example, provides the mono hydrochloridesalt.

Example 472-Chloro-N-(3-(ethyl-(1-methyl-piperidin-4-yl)-amino)-2-fluoro-phenyl)-4-fluoro-benzamide

Heat a mixture ofN-ethyl-2-fluoro-N-(1-methyl-piperidin-4-yl)-benzene-1,3-diamine(Preparation 27) and 2-chloro-4-fluorobenzoyl chloride (23 mg) in1,4-dioxane (5 mL) at reflux for 1 hour. Dilute with methanol (5 mL),load on a SCX column (10 g), wash with methanol, elute the product with2M NH₃ in methanol, evaporate to give the title compound: mass spectrum(electric spray) m/z=408 (M+1). Purify further by HPLC to give thedi-trifluoroacetic acid salt.

Example 482-Chloro-4-fluoro-N-(3-fluoro-5-(methyl-(1-methyl-piperidin-4-yl)-amino)-phenyl)-benzamide

Combine5-fluoro-N-methyl-N-(1-methyl-piperidin-4-yl)-benzene-1,3-diamine(Preparation 29, 0.036 g, 0.15 mmol), 2-chloro-4-fluoro-benzoyl chloride(0.044 g, 0.23 mmol) and 1,4-dioxane (2 mL), stir and heat at reflux.After 3 hr, cool to ambient temperature. Load on a SCX column (10 g),wash with methanol, elute with 2M ammonia-methanol. Concentrate eluentto obtain 0.059 g (100%) the title compound as a free base. Dissolvethis material in dichloromethane (5 mL) and treat with 1M hydrochloricacid in ether (0.15 mL, 0.15 mmol). Concentrate to give the titlecompound as a brown powder: high resolution mass spectrum: Obs. m/z394.1495; Calc. m/z 394.1497; ¹H NMR (CDCl₃) of free base: 7.8 (bs, 1H),7.7 (m, 1H), 7.2 (m, 1H), 7.1 (m, 1H), 6.8 (s, 1H), 6.7 (m, 1H), 6.2 (m,1H), 3.5 (m, 1H), 2.9 (m, 2H), 2.8 (s, 3H), 2.3 (s, 3H), 2.1 (m, 2H),1.9 (m, 2H), 1.7 (m, 2H).

Examples 49-52

Using methods similar to Example 48, the following compounds areprepared, isolated and converted to mono hydrochloric acid salts No ArStructure Data 49 2-(3-bromo- thiophene)

mass spectrum: obs. m/z 426.14; Calc'd m/z 426.06; mp 175-180° C. ¹H NMR(CDCl₃): 10.5 (bs, 1H), 10.3 (s, 1H), 7.9 (d, 1H), 7.3 (d, 1H), 7.0 (m,2H), 6.6 (d, 1H), 4.0 (m, 1H), 3.5 (m, 2H), 3.2 (m, 2H), 2.7 (s, 3H),2.5 (s, 3H), 2.2 (m, 2H), 1.8 (m, 2H). 50 2-chloro- phenyl

mass spectrum: obs. m/z 376.1613, calc'd m/z 376.1592; mp 170-175° C.;Analysis calc'd for C₂₀H₂₄C₁₂FN₃O•0.5H₂O: C, 57.01; H, 5.98; N, 9.97.Found: C, 56.96; H, 5.92; N, 9.96 51 4-fluoro- phenyl

mass spectrum: obs. m/z 360.1890; calc'd m/z 360.1887; mp 175° C.;Analysis calc'd for C₂₀H₂₃F₂N₃O•1.35HCl: C, 58.78; H, 6.01; N, 10.28.Found: C, 58.73; H, 5.95; N, 10.24. 52 2,4-difluoro- phenyl

mass spectrum: obs. m/z 378.25; calc'd m/z 378.17; mp 175° C.; Analysiscalc'd for C₂₀H₂₂F₃N₃O•2.38 HCl: C, 51.75; H. 5.29; N, 9.05. Found: C,51.81; H, 5.14; N, 8.95.

Example 534-Fluoro-N-(3-fluoro-5-(1-methyl-piperidin-4-ylamino)-phenyl)-benzamidedihydrochloride salt

Add slowly 4-fluorobenzoyl chloride (403 mg, 2.54 mmol) to a solution of5-fluoro-benzene-1,3-diamine (Preparation 32, 320 mg, 2.54 mmol) intriethylamine (514 mg, 0.71 mL, 5.08 mmol) and THF (10 mL) at 0° C. Stirthe mixture overnight and gradually raise to room temperature. Quenchthe reaction with 0.1N NaOH solution, and extract the mixture withethylacetate three times. Combine the organic layers and wash withsaturated NaCl solution, dry over Na₂SO₄, filter and concentrate to givea solid.

Purify by chromatography (silica gel, eluting with 25-40% ethylacetatein hexanes) gives 379 mg (60%) ofN-(3-amino-5-fluoro-phenyl)-4-fluoro-benzamide.

Combine the above benzamide (379 mg, 1.53 mmol), 1-methyl-4-piperidone(345 mg, 3.06 mmol), THF (1.5 mL), 1,2-dichloroethane (15 mL), molecularsieve 4A (0.7 g) and acetic acid (276 mg, 0.26 mL, 4.59 mmol). Addsodium triacetoxyborohydride portionwise and stir the mixture at roomtemperature overnight. Quench the reaction with 0.1N NaOH solution,extract the mixture with CH₂Cl₂ three times. Combine the organic layers,dry over Na₂SO₄, filter and concentrate to give a crude residue. Purifyby chromatography (silica gel, eluting with 5.5% 2M NH₃-methanol inCH₂Cl₂) provides 434 mg (82%) of the free base of the title compound:Free base: mass spectrum (ion spray): m/z=346.1; ¹H NMR (CDCl₃, ppm):7.86 (m, 3H), 7.14 (t, 2H), 6.88 (s, br, 1H), 6.60 (dt, 1H), 6.10 (dt,1H), 3.79 (d, 1H), 3.24 (m, 1H), 2.78 (m, 2H), 2.31 (s, 3H), 2.17-2.03(m, 4H), 1.42 (m, 2H). Dissolve the free base in methanol and add 2equivalents of 1 N HCl in diethylether. Remove the solvent and wash withdiethylether. Remove the solvent to obtain the title compound:Di-hydrochloride salt: Anal calculated for C₁₉H₂₁F₂N₃O.2HCl: C, 54.55;H, 5.54; N, 10.04. Found: C, 54.58; H, 5.45; N, 9.84.

Example 542,6-Difluoro-N-(3-fluoro-5-(1-methyl-piperidin-4-ylamino)-phenyl)-benzamidedihydrochloride salt

Using methods similar to example 53, using 2,6-difluorobenzoyl chloride(448 mg, 2.54 mmol) gives 515 mg (56% two-step yield) of the free baseof the title compound. Using a salt formation method similar to thatdescribed in Example 59 gives the title compound: Free base: massspectrum (ion spray): m/z=364.1 (M+1); ¹H NMR (CDCl₃, ppm): 7.63 (s, br,1H), 7.55 (m, 1H), 7.40 (s, 1H), 7.13 (t, 2H), 7.02 (s, br, 1H), 6.67(dt, 1H), 6.24 (dt, 1H), 3.90 (m, 1H), 3.41 (m, 1H), 2.92 (m, 2H), 2.43(s, 3H), 2.22 (m, 4H), 1.60 (m, 2H). Di-hydrochloride salt: Anal calc'dfor C₁₉H₂₀F₃N₃O.2HCl: C, 52.31; H, 5.08; N, 9.63. Found: C, 52.65; H,4.96; N, 9.44.

Example 552,4,6-Trifluoro-N-(3-fluoro-5-(1-methyl-piperidin-4-ylamino)-phenyl)-benzamidehydrochloride salt

Using methods similar to example 53, using 2,4,6-trifluorobenzoylchloride (494 mg, 2.54 mmol) gives 525 mg (54% two-step yield) of thefree base of the title compound. Using a salt formation method similarto that described in Example 59, using 1 equivalent of HCl gives obtainthe title compound: Free base: mass spectrum (ion spray): m/z=382.1(M+1); ¹H NMR (CDCl₃, ppm): 7.87 (s, br, 1H), 6.85 (s, br, 1H), 6.70 (m,2H), 6.54 (m, 1H), 6.11 (dt, 1H), 3.80 (d, 1H), 3.25 (m, 1H), 2.75 (m,2H), 2.30 (s, 3H), 2.16-2.02 (m, 4H), 1.49 (m, 2H). Mono-hydrochloridesalt: Anal calc'd for C₁₉H₁₉F₄N₃O.HCl—H₂O: C, 52.36; H, 5.09; N, 9.64.Found, C, 52.71; H, 4.78; N, 9.62.

Example 562-Chloro-6-fluoro-N-(3-fluoro-5-(1-methyl-piperidin-4-ylamino)-phenyl)-benzamidedihydrochloride salt

Using methods similar to example 53, using 2-chloro-6-fluorobenzoylchloride (490 mg, 2.54 mmol) gives 667 mg (69% two-step yield) of thefree base of the title compound. Using a salt formation method similarto that described in Example 59 gives the title compound: Free base:mass spectrum (ion spray): m/z=380.0 (M+1); ¹H NMR (CDCl₃, ppm): 7.38(m, 2H), 7.28 (m, 1H), m 7.12 (m, 1H), 6.91 (s, br, 1H), 6.56 (dt, 1H),6.14 (dt, 1H), 3.83 (d, 1H), 3.29 (m, 1H), 2.77 (m, 2H), 2.33 (s, 3H),2.20-2.06 (m, 4H), 1.55 (m, 2H). Di-hydrochloride salt: Anal calc'd forC₁₉H₂₀ClF₂N₃O.2HCl.0.4H₂O: C, 49.61; H, 5.00; N, 9.14. Found: C, 49.27;H, 4.55; N, 9.08.

Example 572-Chloro-4-fluoro-N-(3-fluoro-5-(1-methyl-piperidin-4-ylamino)-phenyl)-benzamidedihydrochloride salt

Using methods similar to example 53, using 2-chloro-4-fluorobenzoylchloride (490 mg, 2.54 mmol) gives 654 mg (68% two-step yield) of thefree base of the title compound. Using a salt formation method similarto that described in Example 59 gives the title compound: Free base:mass spectrum (ion spray): m/z=380.0 (M+1); ¹H NMR (CDCl₃, ppm): 7.82(m, 2H), 7.24 (dd, 1H), 7.17 (m, 1H), 6.90 (s, br, 1H), 6.60 (m, 1H),6.15 (dt, 1H), 3.83 (d, 1H), 3.31 (m, 1H), 2.85 (m, 2H), 2.35 (s, 3H),2.23-2.08 (m, 4H), 1.53 (m, 2H). Di-hydrochloride salt: Anal. calc'd.for C₁₉H₂₀ClF₂N₃O.2HCl: C, 50.40; H, 4.89; N, 9.28. Found: C, 50.43; H,4.60; N, 9.29.

Examples 58-65

Examples 58-65 are synthesized by heating5-fluoro-N-methyl-N-(1-methyl-piperidin-4-yl)-benzene-1,3-diamine(Preparation 31, 200 μL of 0.5M solution in dioxane) and the appropriateR-acid chloride (0.10 mmol) to 90° C. for 2 hr. The reaction mixture isdiluted with 10% acetic acid/methanol (0.5 mL). The resulting solutionis directly applied to a 2 g SCX column. After thoroughly washing withmethanol, the column is eluted with 1M ammonia-methanol and the eluantis concentrated and further purified by high-throughput mass guidedchromatography. The compounds are characterized by chromatography usinga Metachem™ C18 column (monochrom 3 micron, 2.5×25 cm) using a 10-90%solvent B gradient in 4.5 min., where solvent A is 0.% trifluoroaceticacid in water and solvent B is 0.1% trifluoroacetic acid inacetonitrile. The procedure is repeated in parallel for Examples 64-71Ex. Structure Name Data 58

2,6-Difluoro-N-(3-fluoro-5-(N′- methyl-N′-(1-methyl-piperidin-4-yl)amino)phenyl)benzamide LCMS Rf 1.54 min at 254 nm, m/e 378 (M + 1).59

3-Chloro-N-(3-fluoro-5-(N′- methyl-N′-(1-methyl-piperidin-4-yl)amino)phenyl)thiopheneamide LCMS Rf 1.72 min at 254 nm, m/e 382(M + 1). 60

2,4,6-Trifluoro-N-(3-fluoro-5- (N′-methyl-N′-(1-methyl- piperidin-4-yl)amino)phenyl)benzamide LCMS Rf 1.61 min at 254 nm, m/e 396 (M + 1). 61

3,4-Difluoro-N-(3-fluoro-5-(N′- methyl-N′-(1-methyl-piperidin-4-yl)amino)phenyl)benzamide LCMS Rf 1.65 min at 254 nm, m/e 378 (M + 1).62

2-Bromo-N-(3-fluoro-5-(N′- methyl-N′-(1-methyl-piperidin-4-yl)amino)phenyl)benzamide LCMS Rf 1.58 min at 254 nm, m/e 422 (M + 1).63

N-(3-fluoro-5-(N′-methyl-N′- (1-methyl-piperidin-4-yl)amino)phenyl)isonicotinamide LCMS Rf 1.24 min at 254 nm, m/e 343 (M +1). 64

2,4-Dichloro-N-(3-fluoro-5-(N′- methyl-N′-(1-methyl-piperidin-4-yl)amino)phenyl)benzamide LCMS Rf 1.73 min at 254 nm, m/e 410 (M + 1).65

2-Chloro-6-fluoro-N-(3-fluoro-5- (N′-methyl-N′-(1-methyl-piperidin-4-yl) amino)phenyl)benzamide LCMS Rf 1.58 min at 254 nm, m/e394 (M + 1).

Example 664-Cyano-N-(6-(1-methylpiperidin-4-ylamino)pyridin-2-yl)benzamidehydrochloride

Combine 4-cyanobenzoyl chloride (300 μL, 1.80 mmol), 2,6-diaminopyridine(600 mg, 5.5 mmol, and dioxane (10 mL); stir at room temperature for 2hr. Pour into water and adjust to pH>12 by the addition of 5N NaOH.Extract with CH₂Cl₂ twice, combine organics, dry over MgSO₄, andconcentrate. Chromatograph (silica gel, eluting with 0-10%methanol/CH₂Cl₂). Dissolve the purified intermediateN-(6-amino-pyridin-2-yl)-4-cyano-benzamide (202 mg, 0.84 mmol, 47%) inTHF (10 mL). Add to this 1-methyl-4-piperidone (77 mg, 0.68 mmol),acetic acid (150 μL, 2.5 mmol), and sodium triacetoxyborohydride (440mg, 2.10 mmol). Stir the reaction at room temperature for 18 hr, andquench by the addition of saturated aqueous NaHCO₃. Extract the aqueouslayer with ethylacetate twice, wash the combined organics with saturatedaqueous NaCl, dry over MgSO₄, and concentrate. Chromatograph thematerial (silica gel, eluting with 0-20% 2M NH₃ in methanol/CH₂Cl₂).Dissolve the clean material (10.4 mg, 5%) in methanol and add 1equivalent (1.7 mg) of NH₄Cl. Sonicate the reaction at room temperaturefor 15 min, then concentrate to provide the title compound: massspectrum (ion spray): m/z=336.0 (M+1).

Example 674-Fluoro-N-(3-(methyl-(1-methyl-piperidin-4-yl)-amino)phenyl)-2-trifluoromethyl-benzamidehydrochloride

A method similar to Example 66, using 4-fluoro-2-trifluoromethylbenzoylchloride, gives the title compound as a white solid (42 mg): massspectrum (ion spray): m/z=397.0 (M+1); mp 84.9° C.

Example 68N-(3-(methyl-(1-methyl-piperidin-4-yl)-amino)phenyl)-2,3,4-trifluoro-benzamidehydrochloride

A method similar to Example 66, using 2,3,4-trifluorobenzoyl chloride,gives the title compound as a white solid (32 mg): mass spectrum (ionspray): m/z=365.3 (M+1); mp 231.4° C. (dec.).

Example 692-Chloro-4-fluoro-N-(6-(methyl-(1-methyl-piperidin-4-yl)-amino)-pyridin-2-yl)-benzamidehydrochloride

Prepare according to procedure in Example 66 starting withN-methyl-N-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation34) (200 mg, 0.907 mmol) and 2-chloro-4-fluorobenzoyl chloride (263 mg,1.36 mmol), and using pyridine as the solvent, to yield 185 mg (49%) ofthe title compound: mass spectrum (ion spray): m/z=377.2 (M+1); Analysiscalc'd for C₁₉H₂₃N₄OFCl₂.0.6H₂O: C, 53.80; H, 5.75; N, 13.21. Found: C,53.55; H, 5.66; N, 13.28; mp 229-31° C.

Example 704-Fluoro-N-(6-(methyl-(1-methyl-piperidin-4-yl)-amino)-pyridin-2-yl)-benzamidehydrochloride

Prepare according to Example 69 starting withN-Methyl-N-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation34) (200 mg, 0.91 mmol) and 4-fluorobenzoyl chloride (160 ut, 1.36 mmol)to yield 309 mg (90%) of the title compound: mass spectrum (ion spray):m/z=343.3 (M+1); Analysis calc'd for C₁₉H₂₄N₄OFCl.0.6H₂O: C, 58.56; H,6.52; N, 14.38. Found: C, 58.31; H, 6.37; N, 14.39; mp 250-2° C.

Example 71N-(6-(Methyl-(1-methylpiperidin-4-yl)amino)pyridin-2-yl)isonicotinamidehydrochloride

Prepare according to procedure in Example 69 starting withN-methyl-N-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation34) (175 mg, 0.794 mmol), isonicotinoyl chloride hydrochloride (212 mg,1.19 mmol), and pyridine (15 mL) to yield 247 mg (86%) of the titlecompound: mass spectrum (ion spray): m/z=326.1 (M+1); Analysis Calcd forC₁₈H₂₄N₅OCl 0.5H₂O: C, 58.29; H, 6.79; N, 18.88. Found: C, 58.49; H,6.79; N, 19.22. mp 274-7° C.

Example 72 Furan-2-carboxylic acid(6-(methyl-(1-methyl-piperidin-4-yl)-amino)-pyridin-2-yl)-amidehydrochloride

Prepare according to procedure in Example 69 starting withN-methyl-N-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation34, 175 mg, 0.794 mmol), 2-furoyl chloride (117 μL, 1.19 mmol), andpyridine (15 mL) to yield 243 mg (87%) of the title compound: massspectrum (ion spray): m/z=315.1 (M+1); Analysis calc'd forC₁₇H₂₃N₄O₂Cl.0.2H₂O: C, 57.60; H, 6.65; N, 15.81. Found: C, 57.31; H,6.72; N, 15.81. mp 116-9° C.

Example 73 Thiophene-2-carboxylic acid(6-(methyl-(1-methyl-piperidin-4-yl)-amino)-pyridin-2-yl)-thiophenamidehydrochloride

Prepare according to procedure in Example 69 starting withN-methyl-N-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation34) (175 mg, 0.794 mmol), thiophene-2-carbonyl chloride (127 μL, 1.19mmol), and pyridine (15 mL) to yield 238 mg (82%) of the title compound:mass spectrum (ion spray): m/z=331.1 (M+1); Analysis Calcd forC₁₇H₂₃N₄OSCl: C, 55.65; H, 6.32; N, 15.27. Found: C, 55.46; H, 6.49; N,15.41. mp 126-8° C.

Example 74N-(6-(methyl-(1-methyl-piperidin-4-yl)-amino)-pyridin-2-yl)-propionamidehydrochloride

Prepare according to procedure in Example 69 starting withN-methyl-N-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation34, 175 mg, 0.794 mmol), propionic anhydride (152 uL, 1.19 mmol), andpyridine (15 mL) to yield 134 mg (54%) of the title compound: massspectrum (ion spray): m/z=277.1 (M+1); Analysis Calcd forC₁₅H₂₅N₄OCl.0.2H₂O: C, 57.11; H, 7.80; N, 17.76. Found: C, 56.73; H,8.16; N, 17.94. mp 216-8° C.

Example 75 Cyclobutanecarboxylic acid(6-(methyl-(1-methyl-piperidin-4-yl)-amino)-pyridin-2-yl)-amidehydrochloride

Prepare according to procedure in Example 69 starting withN-Methyl-N-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation34) (175 mg, 0.794 mmol), cyclobutanecarbonyl chloride (136 μL, 1.19mmol), and pyridine (15 mL) to yield 237 mg (88%) of the title compound:mass spectrum (ion spray): m/z=303.1 (M+1); Analysis Calcd forC₁₇H₂₇N₄OCl.0.1H₂O: C, 59.93; H, 8.05; N, 16.45. Found: C, 59.81; H,7.93; N, 16.45. mp 258-60° C.

Example 76 Cyclohexanecarboxylicacid(6-(methyl-(1-methyl-piperidin-4-yl)-amino)-pyridin-2-yl)-amidehydrochloride

Prepare according to procedure in Example 69 starting withN-methyl-N-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation34, 175 mg, 0.794 mmol), cyclohexanecarbonyl chloride (159 μL, 1.19mmol), and pyridine (15 mL) to yield 257 mg (88%) of the title compound.Mass spectrum (ion spray): m/z 331.2 (M+1); Analysis Calcd forC₁₉H₃₁N₄OCl: C, 62.19; H, 8.51; N, 15.27. Found: C, 61.22; H, 8.44; N,15.39. mp 250-2° C.

Example 77 Cyclopropanecarboxylic acid(6-(methyl-(1-methyl-piperidin-4-yl)-amino)-pyridin-2-yl)-amidehydrochloride

Prepare according to procedure in Example 69 starting withN-methyl-N-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation34, 175 mg, 0.794 mmol), cyclopropanecarbonyl chloride (108 μL, 1.19mmol), and pyridine (15 mL) to yield 190 mg (74%) of the title compound:mass spectrum (ion spray): m/z 289.1 (M+1); Analysis Calc'd forC₁₆H₂₅N₄OCl.0.1H₂O: C, 58.83; H, 7.78; N, 17.15. Found: C, 58.69; H,7.71; N, 17.31. mp 258-60° C.

Example 782,6-Difluoro-N-(6-(methyl-(1-methyl-piperidin-4-yl)-amino)-pyridin-2-yl)-benzamidehydrochloride

Prepare according to procedure in Example 66 starting withN-methyl-N-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation34, 200 mg, 0.907 mmol), 2,6-difluorobenzoyl chloride (125 μL, 0.998mmol), and 1,4-dioxane (10 mL) to yield 289 mg (80%) of the titlecompound: mass spectrum (ion spray): m/z=361.3 (M+1); Analysis Calcd forC₁₉H₂₃N₄OF₂Cl.0.5H₂O: C, 56.22; H, 5.96; N, 13.80. Found: C, 56.49; H,5.80; N, 14.15. mp 308° C. (dec.).

Example 792,4,6-Trifluoro-N-(6-(methyl-(1-methyl-piperidin-4-yl)-amino)-pyridin-2-yl)-benzamidehydrochloride

Prepare according to procedure in Example 66 starting withN-methyl-N-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation34) (200 mg, 0.907 mmol), 2,4,6-trifluorobenzoyl chloride (130, μL,0.998 mmol), and 1,4-dioxane (10 mL) to yield 302 mg (80%) of the titlecompound: mass spectrum (ion spray): m/z=379.2 (M+1); Analysis calc'dfor C₁₉H₂₂N₄OF₃Cl.0.5H₂O: C, 53.84; H, 5.47; N, 13.22. Found: C, 54.02;H, 5.32; N, 13.56. mp 302° C. (dec.).

Example 802-Chloro-N-(6-(methyl-(1-methyl-piperidin-4-yl)-amino)-pyridin-2-yl)-benzamidehydrochloride

Prepare according to procedure in Example 66 starting withN-methyl-N-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation34) (200 mg, 0.907 mmol), 2-chlorobenzoyl chloride (126 μL, 0.998 mmol),and 1,4-dioxane (10 mL) to yield 340 mg (95%) of the title compound:mass spectrum (ion spray): m/z=359.3 (M+1); Analysis calc'd forC₁₉H₂₄N₄OCl₂.0.5H₂O: C, 56.44; H, 6.23; N, 13.86. Found: C, 56.21; H,5.91; N, 14.23. mp 90-2° C.

Example 812-Chloro-6-fluoro-N-(6-(methyl-(1-methyl-piperidin-4-yl)-amino)-pyridin-2-yl)-benzamidehydrochloride

Prepare according to procedure in Example 66 starting withN-methyl-N-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation34) (200 mg, 0.907 mmol), 2-chloro-6-fluorobenzoyl chloride (179 mg,0.998 mmol), and 1,4-dioxane (10 mL) to yield 310 mg (83%) of the titlecompound: mass spectrum (ion spray): m/z=377.2 (M+1); Analysis calc'dfor C₁₉H₂₃N₄OCl₂.0.5H₂O: C, 54.03; H, 5.73; N, 13.27. Found: C, 53.71;H, 5.71; N, 13.45. mp 283-6° C.

Example 824-Fluoro-N-(6-(methyl-(1-methyl-piperidin-4-yl)-amino)-pyridin-2-yl)-2-trifluoromethyl-benzamidehydrochloride

Prepare according to procedure in Example 66 starting withN-methyl-N-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation34) (200 mg, 0.907 mmol), 4-fluoro-2-(trifluoromethyl)benzoyl chloride(165 μL, 1.09 mmol), and 1,4-dioxane (10 mL) to yield 332 mg (82%) ofthe title compound: mass spectrum (ion spray): m/z=410.8 (M+1); Analysiscalc'd for C₂₀H₂₃N₄OClF₄ 1.5H₂O: C, 50.69; H, 5.53; N, 11.82. Found: C,50.66; H, 5.17; N, 12.01. mp 100-2° C.

Example 83N-(6-(Methyl-(1-methyl-piperidin-4-yl)-amino)-pyridin-2-yl)-2-trifluoromethoxy-benzamidehydrochloride

Prepare according to procedure in Example 66 starting withN-methyl-N-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation34) (200 mg, 0.907 mmol), 2-(trifluoromethoxy)benzoyl chloride (175 uL,1.09 mmol), and 1,4-dioxane (10 mL) to yield 357 mg (88%) of the titlecompound: mass spectrum (ion spray): m/z=408.8 (M+1); Analysis calc'dfor C₂₀H₂₃N₄O₂F₃Cl.1.0H₂O: C, 51.89; H, 5.66; N, 12.10. Found: 51.64;5.50; 12.48. mp 102-4° C.

Example 844-Bromo-N-(6-(methyl-(1-methyl-piperidin-4-yl)-amino)-pyridin-2-yl)-benzamidehydrochloride

Prepare according to procedure in Example 66 starting with N-methylN-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation 34) (200mg, 0.907 mmol), 2-bromobenzoyl chloride (142 L, 1.09 mmol), and1,4-dioxane (10 mL) to yield 335 mg (84%) of the title compound: massspectrum (ion spray): m/z=404.3 (M+1); Analysis Calculated forC₁₉H₂₄N₄ObrCl.1.1H₂O: C, 49.65; H, 5.75; N, 12.19. Found: C, 49.39; H,5.51; N, 12.46; mp 121-3° C.

Example 854-Fluoro-N-(6-methyl-piperidin-4-yl-amino)-pyridin-2-yl)-benzamidehydrochloride

Place4-(N-(6-(4-fluorobenzoylamino)pyridin-2-yl)-N-methylamino)piperidine-1-carboxylicacid tert-butyl ester (Preparation 41, 0.94 g, 2.2 mmol) in 20 mL ofCH₂Cl₂ and add trifluoroacetic acid (3.16 mL, 21.9 mmol). Stir for 2 hrthen pour directly on a 10 g SCX column and wash with methanol. Removethe product with 2M NH₃ in methanol and concentrate in vacuo.Chromatograph (silica gel, eluting with 0-20% 2M NH₃ in methanol/CH₂Cl₂)to give 0.54 g (75%) of product. Dissolve the clean material in methanoland add 1 equivalent (87.9 mg) of NH₄Cl. Sonicate the reaction at roomtemperature for 15 min, then concentrate to provide the title compound:mass spectrum (ion spray): m/z=329.3 (M+1); mp 152.4° C.

Example 862-Chloro-4-fluoro-N-(6-methyl-piperidin-4-yl-amino)-pyridin-2-yl)-benzamidehydrochloride

A method similar to Example 85, using4-((6-(2-chloro-4-fluoro-benzoylamino)-pyridin-2-yl)-methyl-amino)-piperidine-1-carboxylicacid tert-butyl ester, (Preparation 42), gives the title compound as awhite solid (720 mg): mass spectrum (ion spray): m/z=363.25 (M+1); mp152.1° C.

Example 87N-(6-((1-Ethyl-piperidin-4-yl)-methyl-amino)-pyridin-2-yl)-4-fluoro-benzamidehydrochloride

Place 4-fluoro-N-(6-methyl-piperidin-4-yl-amino)-pyridin-2-yl)-benzamide(free-based of Example 85, 0.19 g, 0.57 mmol) in 6 mL of1,2-dichloroethane and add acetaldehyde (0.11 mL, 2.3 mmol). Stir for 1hr then add sodium triacetoxyborohydride (0.31 g, 1.4 mmol) and stir for18 hr. Quench with 1N NaOH and dilute with water and CH₂Cl₂. Separateand extract the aqueous layer with CH₂Cl₂ (2 times), combine organics,dry over MgSO₄, and concentrate. Chromatograph (silica gel, eluting with0-10% 2M NH₃ in methanol/CH₂Cl₂) to give 0.119 g (60%) of product.Dissolve the clean material in methanol and add 1 equivalent (17.9 mg)of NH₄Cl. Sonicate the reaction at room temperature for 15 min, thenconcentrate to provide the title compound: mass spectrum (ion spray):m/z=357.3 (M+1); mp 75.6° C.

Example 882-Chloro-N-(6-((1-ethyl-piperidin-4-yl)-methyl-amino)-pyridin-2-yl)-4-fluoro-benzamidehydrochloride

A method similar to Example 87, using2-chloro-4-fluoro-N-(6-methyl-piperidin-4-yl-amino)-pyridin-2-yl)-benzamide(free-based of Example 86), gives the title compound as a yellow-whitesolid (102 mg): mass spectrum (ion spray): m/z=391.3 (M+1); mp 132.9° C.

Example 894-Fluoro-N-(6-(methyl-(1-propyl-piperidin-4-yl)-amino)-pyridin-2-yl)-benzamidehydrochloride

A method similar to Example 87, using4-fluoro-N-(6-methyl-piperidin-4-yl-amino)-pyridin-2-yl)-benzamide(free-based of Example 85), and propionaldehyde in place ofacetaldehyde, gives the title compound as a white solid (77 mg): massspectrum (ion spray): m/z=371.4 (M+1); mp 84.7° C.

Example 902-Chloro-4-fluoro-N-(6-(methyl-(1-propyl-piperidin-4-yl)-amino)-pyridin-2-yl)-benzamidehydrochloride

A method similar to Example 87, using2-chloro-4-fluoro-N-(6-methyl-piperidin-4-yl-amino)-pyridin-2-yl)-benzamide(free-based of Example 86), and propionaldehyde in place ofacetaldehyde, gives the title compound as a white solid (41 mg): massspectrum (ion spray): m/z=405.32 (M+1); mp 258° C. (dec).

Example 91N-(6-((1-Cyclopropylmethyl-piperidin-4-yl)-methyl-amino)-pyridin-2-yl)-4-fluoro-benzamidehydrochloride

A method similar to Example 87, using4-fluoro-N-(6-methyl-piperidin-4-yl-amino)-pyridin-2-yl)-benzamide(free-based of Example 85), and cyclopropane carboxaldehyde in place ofacetaldehyde, gives the title compound as a white solid (130 mg): massspectrum (ion spray) m/z=383.2 (M+1); mp 81.6° C.

Example 922-Chloro-N-(6-((1-cyclopropylmethyl-piperidin-4-yl)-methyl-amino)-pyridin-2-yl)-4-fluoro-benzamidehydrochloride

A method similar to Example 87, using2-chloro-4-fluoro-N-(6-methyl-piperidin-4-yl-amino)-pyridin-2-yl)-benzamide,the free-based product from Example 86, and cyclopropane carboxaldehyde,in place of acetaldehyde, gives the title compound as a white solid (143mg): mass spectrum (ion spray): m/z=417.3 (M+1); mp 257.5° C.

Example 934-Fluoro-N-(6-((1-(2-(1-isopropyl-1H-pyrazol-4-yl)-ethyl)-piperidin-4-yl)-methyl-amino)-pyridin-2-yl)-benzamidehydrochloride

Combine 2-(1-isopropyl-1H-pyrazol-4-yl)-ethanol (Preparation 12, 2 g,12.9 mmol) and triethylamine (3.6 mL, 25.9 mmol) in 30 mL of THF. Addmethanesulfonyl chloride (1.3 mL, 15.6 mmol) and stir for 36 hr. Dilutewith water and ethyl acetate. Separate and extract the aqueous layerwith CH₂Cl₂ (2 times). Combine organics, dry over MgSO₄, and concentratein vacuo. Take a portion of this crude mixture (0.17 g, 0.73 mmol) andcombine with4-fluoro-N-(6-methyl-piperidin-4-yl-amino)-pyridin-2-yl)-benzamide(free-based of Example 85, 0.20 g, 0.60 mmol) in 4 ml of DMF. Addpotassium carbonate (0.25 g, 1.8 mmol) and heat at 80° C. for 18 hr.Cool and dilute with water and CH₂Cl₂. Separate and extract the aqueouslayer with CH₂Cl₂ (2 times). Combine organics, dry over MgSO4, andconcentrate in vacuo. Chromatograph (silica gel, eluting with 0-10% 2MNH₃-methanol/CH₂Cl₂) to give 0.158 g of product (57%). Dissolve thepurified oil in methanol, add NH₄Cl (18.2 mg, 1 eq) as a solid, andsonicate the solution at room temperature for 15 min. Concentrationprovides the title compound: mass spectrum (ion spray): m/z=465.4 (M+1);mp 85.8° C.

Example 942-Chloro-4-fluoro-N-(6-((1-(2-(1-isopropyl-1H-pyrazol-4-yl)-ethyl)-piperidin-4-yl)-methyl-amino)-pyridin-2-yl)-benzamidehydrochloride

Using a method similar to Example 93, using2-chloro-4-fluoro-N-(6-methylpiperidin-4-ylamino)pyridin-2-yl)benzamide(Example 86, 150 mg, 0.4 mmol), gives the title compound as a whitesolid (114 mg): mass spectrum (ion spray): m/z=499.36 (M+1), mp 96.7° C.

Example 952,4,6-Trifluoro-N-(6-(1-methyl-piperidin-4-ylamino)-pyridin-2-yl)-benzamidedihydrochloride

Combine N-(6-amino-pyridin-2-yl)-2,4,6-trifluoro-benzamide (Preparation43, 668 mg, 2.5 mmol), 1-methyl-4-piperidone (566 mg, 5.0 mmol), aceticacid (450 mg, 0.43 mL, 7.5 mmol), molecular sieves 4A (1 g) and1,2-dichloroethane, stir for 30 min at room temperature, then add sodiumtriacetoxyborohydride (1.325 g, 6.25 mmol) portion wise. Add anotherbatch of 1-methyl-piperidone (566 mg, 5.0 mmol) and sodiumtriacetoxyborohydride (1.325 g, 6.25 mmol) if starting benzamide isstill present after overnight reaction. Quench the reaction with 0.1NNaOH solution. Extract the mixture with ethylacetate three times.Combine organic layers, dry over Na₂SO4, filter and concentrate toafford a residue. Chromatography (silica gel, 4% 2M NH₃-methanol inCH₂Cl₂) provides 571 mg (63%) of the free base of the title compound.Dilute the free base in CH₂Cl₂ (1 mL), add 1M HCl/Et₂O (5.6 mL, 5.6mmol), remove the supernatant, wash the white solid with ether fourtimes and dry in vacuum oven to afford 600 mg (88%) of the free base ofthe title compound. Using a salt formation method similar to thatdescribed in Example 53 gives the title compound: Free base: massspectrum (ion spray): m/z 365.0 (M+1); ¹H NMR (CDCl₃, ppm): 8.50 (1H,s), 7.49 (m, 2H), 6.70 (m, 2H), 6.14 (d, 1H), 4.38 (d, 1H), 3.48 (m,1H), 2.78 (m, 2H), 2.28 (s, 3H), 2.05 (m, 4H), 1.51 (m, 2H).Di-hydrochloride salt: Anal calc'd for C₁₈H₁₉F₃N₄0-2HCL: C, 49.44; H,4.84; N, 12.81. Found: C, 49.31; H, 4.96; N, 12.49.

Example 964-Fluoro-N-(6-(1-methyl-piperidin-4-ylamino)-pyridin-2-yl)-benzamidedihydrochloride salt

Dissolve 2,6-diaminopyridine (1.637 g, 15 mmol) in dioxane (15 mL) andcool to 0° C. for 10 min. Add 4-fluorobenzoyl chloride (793 mg, 0.59 mL,5.0 mmol) slowly. After 40 min, remove ice bath and stir the reaction atroom temperature. Use the work-up and purification procedures describedin Preparation 43 to provide N-(6-Amino-pyridin-2-yl)-4-fluoro-benzamideas a slightly yellow solid (1.170 g, 100%): mass spectrum (ion spray):m/z=232.0 (M+1).

Using a method similar to Preparation 43, using the above benzamide (580mg, 2.51 mmol, 493 mg) gives 493 mg (60%) of the title compound as awhite solid. Using a salt formation method similar to that described inExample 53 gives the title compound: Free base: mass spectrum (ionspray): m/z=329.2 (M+1); ¹H NMR (CDCl₃, ppm): 8.16 (s, 1H), 7.93 (m,2H), 7.53 (m, 2H), 7.22 (m, 2H), 6.20 (d, 1H), 4.30 (d, 1H), 3.62 (m,1H), 2.80 (m, 2H), 2.33 (s, 3H), 2.16 (m, 4H), 1.53 (m, 2H).Di-hydrochloride salt: Anal calc'd for C₁₈H₂₁FN₄O.2HCl—H₂O: C, 51.56; H,6.01; N, 13.36. Found: C, 51.78; H, 5.65; N, 13.36.

Example 97 N-(6-(1-Methyl-piperidin-4-ylamino)-pyridin-2-yl)-acetamidedihydrochloride salt

Using a method similar to Example 95 and THF as the reaction solvent (40mL), using N-(6-amino-pyridin-2-yl)-acetamide (Preparation 44, 1.512 g,10 mmol) gives 597 mg (24%) of the free base of the title compound.Using a salt formation method similar to that described in Example 53gives the title compound: Free base: mass spectrum (ion spray):m/z=249.1 (M+1); ¹H NMR (CDCl₃, ppm): 7.60 (s, br, 1H), 7.44 (m, 2H),6.14 (m, 1H), 4.25 (d, 1H), 3.58 (m, 1H), 2.84 (m, 2H), 2.34 (s, 3H),2.19 (s, 3H), 2.13 (m, 4H), 1.56 (m 2H). Di-hydrochloride salt: Analcalc'd for C₁₃H2ON₄O-2HCl-0.25H₂O: C, 47.93; H, 6.96; N, 17.20. Found:C, 47.94; H, 7.18; N, 16.77.

Example 982-Chloro-N-(6-(1-methyl-piperidin-4-ylamino)-pyridin-2-yl)-benzamidedihydrochloridesalt

Using a method similar to Example 95 with 1,2-dichloroethane/THF assolvent (1:1, 20 mL), using N-(6-amino-pyridin-2-yl)-2-chloro-benzamide(Preparation 45, 500 mg, 2.02 mmol) gives 285 mg (34%) of the free baseof the title compound as a white solid. Using a salt formation methodsimilar to that described in Example 53 gives the title compound: Freebase: mass spectrum (ion spray): m/z=345.1 (M+1); ¹H NMR (CDCl₃, ppm):8.21 (s, 1H), 7.70 (m, 1H), 7.62 (m, 1H), 7.40 (m, 4H), 6.19 (d, 1H),4.32 (d, 1H), 3.57 (m, 1H), 2.79 (m, 2H), 2.31 (s, 3H), 2.10 (m, 4H),1.51 (m, 2H). Di-hydrochloride salt: Anal calc'd for C₁₈H₂₁ClN₄O.2HCl:C, 51.75; H, 5.55; N, 13.41. Found: C, 51.47; H, 5.38; N, 13.18.

Example 992-Bromo-N-(6-(1-methyl-piperidin-4-ylamino)-pyridin-2-yl)-benzamidedihydrochloridesalt

Using a method similar to Example 98, usingN-(6-amino-pyridin-2-yl)-2-bromo-benzamide (Preparation 46, 495 mg, 1.69mmol) gives 195 mg (25%) of the free base of the title compound as awhite solid. Using a salt formation method similar to that described inExample 53 gives the title compound: Free base: mass spectrum (ionspray): m/z=389.1 (M+1); ¹H NMR (CDCl₃, ppm): 8.09 (s, 1H), 7.64 (m,3H), 7.40 (m, 3H), 6.19 (d, 1H), 4.31 (d, 1H), 3.58 (m, 1H), 2.80 (m,2H), 2.30 (s, 3H), 2.07 (m, 4H), 1.54 (m, 2H). Di-hydrochloride salt:Anal calc'd for C₁₈H₂₁BrN₄O.2HCl-0.5H₂O: C, 45.88; H, 5.13; N, 11.89.Found: C, 45.95; H, 5.10; N, 11.73.

Example 100 Cyclohexanecarboxylic acid(6-(1-methyl-piperidin-4-ylamino)-pyridin-2-yl)-amide dihydrochloridesalt

Using a method similar to Example 98, using cyclohexanecarboxylic acid(6-amino-pyridin-2-yl)-amide (Preparation 47, 510 mg, 2.33 mmol) gives352 mg (39%) of the free base of the title compound. Using a saltformation method similar to that described in Example 53 gives the titlecompound: Free base: mass spectrum (ion spray): m/z=317.2 (M+1); ¹H NMR(CDCl₃, ppm): 7.52 (s, br, 1H), 7.46 (m, 2H), 6.13 (dd, 1H), 4.24 (d,1H), 3.58 (m, 1H), 2.82 (m, 2H), 2.33 (s, 3H), 2.24-1.94 (m, 7H), 1.83(m, 2H), 1.74 (m, 1H), 1.58 (m, 4H), 1.27 (m, 3H). Di-hydrochloridesalt: Anal cald for C₁₈H₂₈N₄O-2HCl-0.5H₂O: C, 54.27; H, 7.84; N, 14.06.Found: C, 54.36; H, 7.83; N, 13.91.

Example 101 2-Chloro-6-fluoro-N(6-(1-methylpiperidin-4-ylamino)pyridin-2-yl)benzamide, free base anddihydrochloride salt

Under an inert atmosphere, stir a mixture ofN-(6-aminopyridin-2-yl)-2-chloro-6-fluorobenzamide (Preparation 48, 810mg, 3.0 mmol), 1-methyl-4-piperidone (339 mg, 0.37 mL, 3.0 mmol),anhydrous THF (50 mL), glacial acetic acid (0.52 mL, 9.2 mmol) at roomtemperature for 45 min. Add sodium triacetoxyborohydride (1 g, 4.6mmol). Allow the reaction to go for 4 days. Transfer the reactionmixture into ethyl acetate (200 mL), then wash once with aqueous NaOH(2N, 30 mL). Separate the organic layer, dry over anhydrous sodiumsulfate. Remove the solvent under reduced pressure. Clean the residue bychromatography (silica gel; 4%-6% (2M NH₃ in methanol)/CH₂Cl₂). Collectthe free base product and convert to its dihydrochloride salt bytreating it in CH₂Cl₂ with excess solution of 1.0M HCl in diethyl etherand adding more ether to cause its precipitation as a white solid (268mg, 20% yield): mass spectrum (ion spray): m/z=363.2 (M+1); Anal.calculated. for C₁₈H2OClFN₄O.2HCl.H₂O: C, 47.64; H, 5.33; N, 12.35.Found: C, 47.69; H, 5.59; N, 11.85; ¹H NMR δ (methanol-d₄) 8.01 (dd,1H), 7.60 (q, 1H), 7.44 (d, 1H), 7.31 (t, 1H), 6.91 (d, 1H), 6.65 (d,1H), 3.98 (m, 1H), 3.64 (d, 2H), 3.30 (dd, 2H), 2.91 (s, 3H), 2.37 (d,2H), 1.93 (m, 2H)

Example 1023-Chloro-2,6-difluoro-N-(6-(1-methylpiperidin-4-ylamino)pyridin-2-yl)benzamideand dihydrochloride salt

Using a method similar to Example 101, usingN-(6-Aminopyridin-2-yl)-3-chloro-2,6-difluorobenzamide (Preparation 49,764 mg, 2.7 mmol), 1-methyl-4-piperidone (305 mg, 0.3 mL, 2.7 mmol),anhydrous THF (50 mL), glacial acetic acid (0.46 mL, 8.1 mmol), sodiumtriacetoxyborohydride (848 mg, 4.0 mmol) gives the title compound(dihydrochloride salt: 335 mg, 27% yield): mass spectrum (ion spray):m/z=381.0 (M+1); Anal. calc'd. for C₁₈H₁₉ClF₂N₄O.2HCl.H₂O: C, 45.83; H,4.91; N, 11.88. Found: C, 46.33; H, 5.02; N, 11.36; (LY 635146) ¹H NMR δ(methanol-d₄) 7.99 (dd, 1H), 7.77 (m, 1H), 7.23 (t, 1H), 6.91 (d, 1H),6.69 (d, 1H), 3.98 (m, 1H), 3.64 (d, 2H), 3.30 (dd, 2H), 2.91 (s, 3H),2.37 (d, 2H), 1.93 (m, 2H).

Example 1032,6-Difluoro-3-methyl-N-(6-(1-methylpiperidin-4-ylamino)pyridin-2-yl)benzamideand dihydrochloride salt

Using a method similar to Example 101, usingN-(6-Aminopyridin-2-yl)-2,6-difluoro-3-methylbenzamide (Preparation 50,662 mg, 2.5 mmol), 1-methyl-4-piperidone (282 mg, 0.26 mL, 2.5 mmol),anhydrous THF (50 mL), glacial acetic acid (0.42 mL, 7.5 mmol), sodiumtriacetoxyborohydride (795 mg, 3.75 mmol) gives the title compound(dihydrochloride salt: (208 mg, 19% yield): mass spectrum (ion spray):m/z=361.1 (M+1); Anal. calc'd. for C₁₉H₂₂F₂N₄O 2HCL: C, 52.66; H, 5.58;N, 12.93. Found: C, 52.70; H, 5.46; N, 12.75; ¹H NMR δ (methanol-d₄)8.02 (dd, 1H), 7.51 (q, 1H), 7.09 (t, 1H), 6.90 (d, 1H), 6.63 (d, 1H),3.98 (m, 1H), 3.64 (d, 2H), 3.30 (dd, 2H), 2.91 (s, 3H), 2.37 (d, 2H),2.31 (s, 3H), 1.93 (m, 2H)

Example 1042-Chloro-4-fluoro-N-(6-(1-methylpiperidin-4-ylamino)pyridin-2-yl)benzamideand dihydrochloride salt

Under an inert atmosphere, stir a mixture ofN-(6-aminopyridin-2-yl)-2-chloro-4-fluorobenzamide (Preparation 38, 433mg, 1.63 mmol), 1-methyl-4-piperidone (369.5 mg, 0.4 mL, 3.27 mmol),1,2-dichloroethane (20 mL), powdered molecular sieves 4A (1 g) for 15min. Add glacial acetic acid (294 mg, 0.28 mL, 4.89 mmol). After 1 hr.add sodium triacetoxyborohydride (869 mg, 4.1 mmol). Allow the reactionto go overnight. transfer the reaction mixture into ethyl acetate (200mL), then wash once with aqueous NaOH (2N, 30 mL). Separate the organiclayer, dry over anhydrous sodium sulfate, pull off the solvent underreduced pressure. Clean the residue by chromatography (silica gel; 5%-6%(2M NH₃ in methanol)/CH₂Cl₂). Collect the free base product (226 mg, 38%yield). Convert the product to its dihydrochloride salt by treating itin CH₂Cl₂ with excess solution of 1.0M HCl in diethyl ether and addingmore ether to cause its precipitation as a white solid: mass spectrum(ion spray): m/z=363.0 (M+1); Anal. calculated forC₁₈H₂₀ClFN₄O.2HCl.0.5H₂O: C, 48.61; H, 5.21; N, 12.60. Found: C, 48.43;H, 5.11; N, 12.28; (LY 635148) ¹H NMR δ (methanol-d₄) 8.00 (dd, 1H),7.77 (m, 1H), 7.45 (d, 1H), 7.29 (m, 1H), 6.90 (d, 1H), 6.65 (d, 1H),3.98 (m, 1H), 3.64 (d, 2H), 3.30 (dd, 2H), 2.91 (s, 3H), 2.37 (d, 2H),1.93 (m, 2H)

Example 1052,4-Difluoro-N-(6-(1-methylpiperidin-4-ylamino)pyridin-2-yl)benzamideand dihydrochloride salt

Using a method similar to Example 101, usingN-(6-aminopyridin-2-yl)-2,4-difluorobenzamide (Preparation 51, 617 mg,2.48 mmol), 1-methyl-4-piperidone (280 mg, 0.3 mL, 2.48 mmol), anhydrousTHF (50 mL), glacial acetic acid (0.42 mL, 7.4 mmol), sodiumtriacetoxyborohydride (784 mg, 3.7 mmol) gives the title compound(dihydrochloride salt: 56.4 mg, 5% yield): mass spectrum (ion spray):m/z=347.3 (M+1); Anal. calc'd. for C₁₈H2OF₂N₄O.2HCl.0.5H₂O: C, 50.48; H,5.41; N, 13.08. Found: C, 50.63; H, 5.43; N, 12.84; (LY 635150) ¹H NMR δ(methanol-d₄) 7.95 (m, 2H), 7.20 (m, 2H), 6.86 (d, 1H), 6.73 (d, 1H),3.98 (m, 1H), 3.64 (d, 2H), 3.30 (dd, 2H), 2.91 (s, 3H), 2.37 (d, 2H),1.93 (m, 2H)

Example 1062,6-Dichloro-N-(6-(1-methylpiperidin-4-ylamino)pyridin-2-yl)benzamideand its dihydrochloride salt

Using a method similar to Example 104 usingN-(6-aminopyridin-2-yl)-2,6-dichlorobenzamide (Preparation 52, 569 mg,2.0 mmol), 1-methyl-4-piperidone 450 mg, 0.5 mL, 4.0 mmol),1,2-dichloroethane (15 mL), powdered molecular sieves 4A (1 g), glacialacetic acid (360 mg, 0.34 mL, 6.0 mmol), sodium triacetoxyborohydride(1.06 g, 5.0 mmol) gives the title compound (491 mg, 66% yield):dihydrochloride salt: mass spectrum (ion spray): m/z=379.2 (M+1); Anal.calc'd. for C₁₈H2OCl₂N₄O.2HCl: C, 47.81; H, 4.90; N, 12.39. Found: C,47.59; H, 5.21; N, 12.00; (LY 641053) ¹H NMR δ (CDCl₃) 7.79 (s, 1H),7.59 (d, 1H), 7.47 (t, 1H), 7.34 (m, 3H), 6.18 (d, 1H), 4.26 (d, 1H),3.55 (m, 1H), 2.73 (d, 2H), 2.28 (s, 3H), 2.11 (m, 4H), 1.50 (m, 2H)

Example 1072,6-Difluoro-N-(6-(1-methylpiperidin-4-ylamino)pyridin-2-yl)benzamideFree base and dihydrochloride salt

Using a method similar to Example 104 usingN-(6-aminopyridin-2-yl)-2,6-difluorobenzamide (Preparation 53, 536 mg,2.2 mmol), 1-methyl-4-piperidone (486 mg, 0.53 mL, 4.3 mmol),1,2-dichloroethane (15 mL), powdered molecular sieves 4 Å (1 g), glacialacetic, acid (396 mg, 0.38 mL, 6.6 mmol), sodium triacetoxyborohydride(1.16 g, 5.5 mmol) gives the title compound (596 mg, 78% yield):dihydrochloride salt: mass spectrum (ion spray): m/z=347.2 (M+1); Anal.calc'd. for C₁₈H2OF₂N₄O.2HCl.0.5H₂O: C, 50.48; H, 5.41; N, 13.08. Found:C, 50.76; H, 5.77; N, 12.70; ¹H NMR δ (CDCl₃) 7.94 (s, 1H), 7.55 (d,1H), 7.41 (m, 2H), 6.97 (t, 2H), 6.18 (d, 1H), 4.26 (d, 1H), 3.55 (m,1H), 2.73 (d, 2H), 2.28 (s, 3H), 2.11 (m, 4H), 1.50 (m, 2H)

Example 1082,4-Dichloro-N-(6-(1-methyl-piperidin-4-ylamino)-pyridin-2-yl)-benzamideFree base and dihydrochloride salt

Using a method similar to Example 104 usingN-(6-aminopyridin-2-yl)-2,4-dichlorobenzamide (Preparation 54, 621 mg,2.24 mmol), 1-methyl-4-piperidone (510 mg, 0.55 mL, 4.48 mmol),1,2-dichloroethane (15 mL), powdered molecular sieves 4 Å (1 g), glacialacetic acid (403.5 mg, 0.38 mL, 6.72 mmol), sodium triacetoxyborohydride(1.2 g, 5.6 mmol) gives the title compound (397 mg, 46% yield):dihydrochloride salt: mass spectrum (ion spray): m/z=379.0 (M+1); Anal.calc'd. for C₁₈H2OCl₂N₄O-2HCl.0.4H₂O: C, 47.06; H, 5.00; N, 12.20.Found: C, 47.49; H, 5.31; N, 11.72; ¹H NMR δ (methanol-d₄) 8.01 (dd,1H), 7.69 (m, 2H), 7.53 (d, 1H), 6.90 (d, 1H), 6.67 (m, 1H), 3.98 (m,1H), 3.64 (d, 2H), 3.30 (dd, 2H), 2.91 (s, 3H), 2.37 (d, 2H), 1.93 (m,2H).

Example 1092,4,6-Trichloro-N(6-(1-methylpiperidin-4-ylamino)pyridin-2-yl)benzamideFree base and HCL salt

Using a method similar to Example 104 usingN-(6-amino-pyridin-2-yl)-2,4,6-trichloro-benzamide (Preparation 55, 375mg, 1.18 mmol), 1-methyl-4-piperidone (270 mg, 0.29 mL, 2.37 mmol),1,2-dichloroethane (15 mL), powdered molecular sieves 4 Å (1 g), glacialacetic acid (0.21 g, 0.20 mL, 3.54 mmol), sodium triacetoxyborohydride(625 mg, 2.95 mmol) gives the title compound (187 mg, 45% yield):dihydrochloride salt: mass spectrum (ion spray): m/z=412.0 (M+1), ¹H NMRδ (CDCl₃) 7.78 (s, 1H), 7.56 (d, 1H), 7.45 (t, 1H), 7.36 (s, 2H), 6.18(d, 1H), 4.26 (d, 1H), 3.55 (m, 1H), 2.73 (d, 2H), 2.28 (s, 3H), 2.11(m, 4H), 1.50 (m, 2H).

Examples 110-115

For Examples 110-115, heatN-methyl-N-(1-methylpiperidin-4-yl)-pyridine-2,6-diamine (Preparation34, 200 μL of 0.5M solution in dioxane) and the appropriate R-acidchloride (0.10 mmol) to 90° C. for 2 hr. The reaction mixture is dilutedwith 10% acetic acid/methanol (0.5 mL). The resulting solution isdirectly applied to a 2 g SCX column. After thoroughly washing withmethanol, the column is eluted with 1M ammonia-methanol and the eluantis concentrated and further purified by high-throughput mass guidedchromatography. The compounds are characterized by chromatography usinga Metachem™ C18 column (monochrom 3 micron, 2.5×25 cm) using a 10-90%solvent B gradient in 4.5 min., where solvent A is 0.1% trifluoroaceticacid in water and solvent B is 0.1% trifluoroacetic acid inacetonitrile. The procedure is repeated in parallel for Examples110-115. Ex. Structure Name Data 110

3-Chloro-N-(6-(N′-methyl-N′- (1-methylpiperidin-4-yl)amino)pyridin-2-yl) thiopheneamide LCMS Rf 1.47 Min. at 254 nm, m/e 365(M + 1). 111

2,4-Difluoro-N-(6-(N′-methyl- N′-(1-methylpiperidin-4-yl)amino)pyridin-2-yl)benzamide LCMS Rf 1.36 min. at 254 nm, m/e 361(M + 1). 112

3,4-Difluoro-N-(6-(N′-methyl- N′-(1-methylpiperidin-4-yl)amino)pyridin-2-yl)benzamide LCMS Rf 1.46 min. at 254 nm, m/e 361(M + 1). 113

2,3,4-Trifluoro-N-(3-fluoro-5- (N′-methyl-N′-(1-methyl- piperidin-4-yl)amino)phenyl)benzamide LCMS Rf 1.46 min. at 254 nm, m/e 379 (M + 1). 114

N-(6-(N′-methyl-N′-(1- methylpiperidin-4-yl) amino)pyridin-2-yl)nicotinamide LCMS Rf 1.05 min. at 254 nm, m/e 326 (M + 1). 115

2,4-Dichloro-N-(3-fluoro-5-(N′- methyl-N′-(1-methyl-piperidin-4-yl)amino)phenyl)benzamide LCMS Rf 1.54 min. at 254 nm, m/e 393 (M +1).

The compounds of this invention are useful for increasing activation ofthe 5-HT_(1F) receptor. An increase in the activation of the 5-HT_(1F)is useful for treating a variety of disorders which have been linked todecreased neurotransmission of serotonin in mammals, e.g., migraineheadaches. See U.S. Pat. No. 5,708,008 demonstrating the nexus betweenactivation of the 5-HT_(1F) receptor and migraine. 5-HT_(1F) receptorbinding affinity is determined to demonstrate the use of the compoundsof the present invention in the treatment of migraine. The ability ofthe compounds of this invention to bind to the 5-HT_(1F) receptorsubtype is measured essentially as described in N. Adham, et al.,Proceedings of the National 15 Academy of Sciences (USA), 90: 408-412,1993.

Membrane Preparation:

Prepare membranes from transfected Ltk-cells (transfected with the human5-HT_(1F) receptor sequence) that have grown to 100% confluency. Washthe cells twice with phosphate-buffered saline, scrape them from theculture dishes into 5 mL of ice-cold phosphate-buffered saline, andcentrifuge at 200×g for 5 min. at 4° C. Resuspend the pellet in 2.5 mLof ice-cold Tris buffer (20 mM Tris HCl, pH 7.4 at 23° C., 5 mM EDTA)and homogenize with a Wheaton tissue grinder. Centrifuge the lysate at200×g for 5 min. at 4° C. to pellet large fragments which are discarded.Collect the supernatant and centrifuge at 40,000×g for 20 min. at 4° C.Wash the resulting pellet once in ice-cold Tris wash buffer andresuspend in a final buffer containing 50 mM Tris HCl and 0.5 mM EDTA,pH 7.4 at 23° C. Maintain the membrane preparations on ice and utilizethem for the radioligand binding assays within two hr. of preparation.Determine protein concentrations by the method of Bradford. Anal.Biochem., 72: 248-254, 1976.

Radioligand Binding:

[³H] 5-HT binding is performed using slight modifications of the5-HT_(1D) assay conditions reported by Herrick-Davis and Titeler (J.Neurochem., 50: 1624-1631, 1988) with the omission of masking ligands.Conduct radioligand binding studies at 37° C. in a total volume of 250μL of buffer (50 mM Tris, 10 mM MgCl₂, 0.2 mM EDTA, 10 μM pargyline,0.1% ascorbate, pH 7.4 at 37° C.) in 96 well microtiter plates. Performsaturation studies using [³H] 5-HT at 12 different concentrationsranging from 0.5 nM to 100 nM. Perform displacement studies using4.5-5.5 nM [³H] 5-HT. Use 6-12 concentrations of compound to obtainbinding profiles of drugs in competition experiments. Incubations arefor 30 minutes for both saturation and displacement studies based uponinitial investigations which determined equilibrium binding conditions.Define nonspecific binding in the presence of 10 μM 5-HT. Initiatebinding by the addition of 50 μL membrane homogenate (10-20 μg).Terminate the reaction by rapid filtration through presoaked (0.5%polyethyleneimine) filters using 48R Brandel Cell Harvester(Gaithersburg, Md.). Wash the filters for 5 seconds with ice cold buffer(50 mM Tris HCl, pH=7.4 at 4° C.), dry the filters, and place themindividually into vials containing 2.5 mL Readi-Safe (Beckman,Fullerton, Calif.) and radioactivity was measured using a Beckman LS5000TA liquid scintillation counter. The efficiency of counting of [³H]5-HT averages between 45-50%. Analyze the binding data bycomputer-assisted nonlinear regression analysis (Accufit and Accucomp,Lunden Software, Chagrin Falls, Ohio). Convert the IC₅₀ values to K_(i)values using the Cheng-Prusoff equation. Biochem. Pharmacol., 22:3099-3108 (1973). Perform experiments in triplicate. Representativecompounds of the present invention were assayed essentially as describedabove and were found to have high affinity for the 5-HT_(1F) receptor,as for example K_(i)'s of less than or equal to about 600 nM. Preferredcompounds of the present invention have K_(i)'s of less than or equal toabout 300 nM. Yet more preferred compounds are those having a K_(i) ofless than or equal to about 200 nM. Particularly preferred compounds arethose having a K_(i) of less than or equal to about 50 nM. Exemplifiedcompounds have K_(i)'s of less than or equal to about 200 nM.

Measurement of cAMP Formation

As was reported by R. L. Weinshank, et al., WO93/14201, the 5-HT_(1F)receptor is functionally coupled to a G-protein as measured by theability of serotonin and serotonergic drugs to inhibit forskolinstimulated cAMP production in NIH3T3 cells transfected with the5-HT_(1F) receptor. Adenylate cyclase activity is determined usingstandard techniques. A maximal effect is achieved by serotonin. AnE_(max), is determined by dividing the inhibition of a test compound bythe maximal effect and determining a percent inhibition. N. Adham, etal., supra; R. L. Weinshank, et al., Proceedings of the National Academyof Sciences (USA), 89: 3630-3634, 1992; and the references citedtherein.

Incubate human 5-HT_(1F), receptor transfected NIH3T3 cells (estimatedB_(max) from one point competition studies=488 fmol/mg of protein) inDMEM, 5 mM theophylline, 10 mM HEPES(4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) and 10 uM pargylinefor 20 minutes at 37° C., 5% CO₂. Use a range of 6 final concentrationsof test compound in parallel incubations to obtain drug dose-effectcurves. Obtain a dose-response curve for 5-HT measured in parallel,using a fixed dose of methiothepin (0.32 μM), for use in demonstratingcompetitive antagonism. Add the test compound or 5-HT to the cells, andfollow immediately with the addition of forskolin (10 uM) to initiatestimulated cAMP production. Incubate the cells for 10 minutes at 37° C.,5% CO₂. Aspirate the medium and quench the reaction with 100 mM HCl.Cool the plates at 4° C. for 15 min., centrifuge to pellet cellulardebris (5 min., 500×g), aliquot the supernatant into vials and store at−20° C. until assessment of cAMP formation by radioimmunoassay (cAMPradioimmunoassay kit; Advanced Magnetics, Cambridge, Mass.). Quantifyradioactivity using a Packard COBRA Auto Gamma counter, equipped withdata reduction software. Representative compounds of the presentinvention were assayed essentially as described above and found to beagonists of the 5-HT_(1F) receptor.

Protein Extravasation Assay

The inhibition of neuronal protein extravasation is a functional assayfor the neuronal mechanism of migraine. A compound's ability to inhibitneuronal protein extravasation can be tested as described in thefollowing assay.

Anesthetize Harlan Sprague-Dawley rats (225-325 g) or guinea pigs fromCharles River Laboratories (225-325 g) with sodium pentobarbital(intraperitoneal injection, 65 mg/kg or 45 mg/kg, respectively). Foreach animal, place the animal in a stereotaxic frame (David KopfInstruments) with the incisor bar set at −3.5 mm for rats or −4.0 mm forguinea pigs. Make a midline sagital scalp incision, and drill two pairsof bilateral holes through the skull (6 mm posterially, 2.0 and 4.0 mmlaterally on both sides of the mid-line in rats; 4 mm posteriorly and3.2 and 5.2 mm laterally on both sides of the mid-line in guinea pigs,all coordinates referenced to bregma.). Lower pairs of stainless steelstimulating electrodes, insulated except at the ends (Rhodes MedicalSystems, Inc.), through the holes in both hemispheres, one electrode toa hole, to a depth of 9 mm (rats) or 10.5 mm (guinea pigs) from dura.

Expose the femoral vein and inject a dose of the test compound or salinenegative control intravenously (1 mL/kg). Approximately 7 min. later,inject a 50 mg/kg dose of Evans Blue intravenously. The Evans Blue is afluorescent dye which complexes with proteins in the blood and functionsas a marker for protein extravasation. Exactly 10 min. post-injection ofthe test compound, stimulate the left trigeminal ganglion for 3 min. ata current intensity of 1.0 mA (5 Hz, 4 msec duration) with a Model 273potentiostat/galvanostat (EG&G Princeton Applied Research).

Fifteen minutes following stimulation, kill the animal by exsanguinationwith 20 mL of saline. Remove the top of the skull to facilitate thecollection of dural membrane samples. Remove the membrane samples fromboth hemispheres, rinse with water, spread flat on microscope slides,dry the tissue on a microscope slide warmer, and apply a coverslip witha 70% glycerol/water solution.

Quantify the amount of Evans Blue dye in each sample using afluorescence microscope (Zeiss) equipped with a grating monochronomator,a spectrophotometer, a computer-driven motorized stage, and an interfaceto a personal computer. For each dural membrane sample, measurefluorescence at 25 points (500, μm steps covering a 2.5×2.5 mm squarearea) using an excitation wavelength of approximately 535 nm andmeasuring the emission intensity at a wavelength of 600 nm. Determinedthe mean and standard deviation of these measurements.

The extravasation induced by the electrical stimulation of thetrigeminal ganglion is an ipsilateral effect (i.e. occurs only on theside of the dura in which the trigeminal ganglion was stimulated). Thisallows the stimulated dura to be used as the test tissue and theunstimulated half of the dura to be used as a control. The ratio of theamount of extravasation in the dura from the stimulated side compared tothe unstimulated side is calculated. Saline controls yield a ratio ofapproximately 2.0 in rats and 1.8 in guinea pigs. In contrast, acompound which effectively prevents the extravasation in the dura fromthe stimulated side will have a ratio of approximately 1.0. Using arange of compound doses and multiple animals at each dosage level,generate a dose-response curve for the test compound and approximate thedose that inhibits the extravasation by 50% (ID₅₀). Representativecompounds of the present invention were assayed essentially as describedabove. The compounds were found to significantly inhibit neuronalprotein extravasation and are thus efficatious in the neurogenic plasmaprotein extravasation model for migraine.

Rabbit Saphenous Vein Contraction

Sacrifice male New Zealand White rabbits (3-6 lbs) (Hazleton, Kalamazoo,Mich.) by a lethal dose of sodium pentobarbital (325 mg) injected intothe ear vein. Dissect saphenous vein tissue free of connective tissue,cannulate in situ with polyethylene tubing (PE50, outside diameter=0.97mm) and place in petri dishes containing modified Kreb's solution (118.2mMol NaCl, 4.6 mMol KCl, 1.6 mMol CaCI₂.H₂O, 1.2 mMol KH₂PO₄, 1.2 mMolMgSO₄, 10.0 mMol dextrose and 24.8 mMol NaHCO₃). Bend the tips of two30-gauge stainless steel hypodermic needles into an L-shape and slipthem into the lumen of the polyethylene tubing. Gently push vein tissuefrom the cannula onto the needles. Separate the needles and attach thelower needle with thread to a stationary glass rod and the upper needlewith thread to a force transducer (Statham UC-3).

Mount the tissues in organ baths containing 10 mL of modified Krebs'solution. Maintain tissue bath solutions at 37° C. and aerate with 95%O₂ and 5% CO₂. Apply an initial optimum resting force of 4 grams to thevein tissue. Record isometric contractions as changes in grams of forceon a Beckman Dynograph with Statham UC-3 transducers and microscaleaccessory attachments. Allow tissues to equilibrate 1 to 2 hr. beforeexposure to test compound. Add 67 mM KCl to the bath and record themaximal contraction. Flush the bath, allow the tissue to re-equilibrateunder a 4 gram force, add test compound and record the force ofcontraction. Add additional compound to achieve the next concentrationin a range of compound concentrations to generate cumulative agonistconcentration-response curves for each test compound. Tissues can beused to generate up to two agonist concentration-response curves.Calculate the mean EC₅o and the maximal compound response, which maximumis expressed as a percentage of the maximal contraction for the tissuein response to the 67 mM KCl administered initially to each tissue.

Two important parameters can be measured with this vasoconstrictionassay, saphenous vein contraction (EC₅₀) and maximal contraction as apercentage of the maximal KCl response (%_(max) KCl). The saphenous veincontraction (EC₅₀) is a measure of the dose required to contract tissueto 50% of the maximal response that the specific compound is capable ofmediating. The maximal response that the saphenous vein is capable ofexhibiting is measured after administration of a high concentration (67mM) of KCl. The %_(max) KCl contraction is the ratio of the maximalresponse that the specific compound is capable of mediating divided bythe maximal response that the tissue can produce upon stimulation withKCl. For purposes of this application, a compound may be considered tonot have significant vasoconstrictive activity if it produces a maximalcontraction of less than or equal to 5% of the contraction produced bythe 67 mM KCl positive control at a compound concentration of up to 100μM, when assayed essentially as described above.

Representative compounds of the present invention were tested forvasoconstrictive activity in the rabbit saphenous vein assay essentiallyas described above and were found to not be significantlyvasoconstrictive. All compounds of the present invention that weretested had a % max KCl less than or equal to 10%. This contrasts greatlywith prior art compounds for the treatment of migraine targeting theneural vasoconstrictive model for migraine treatment, which compoundswere selected on the basis of strong vasoconstrictive activity, as forexample, sumatriptan, which has an EC₅o of 0.66 mM and a %_(max) KCl of64.20 when tested essentially as described above.

Selectivity for the 5-HT_(1F) Receptor

Compounds of the prevent invention are relatively selective for the5-HT_(1F) receptor, particularly in comparison to other 5-HT receptorsubtypes, specifically other receptors in the 5-HT₁ subclass, as forexample, but without limitation, the 5-HT_(1A), 5-HT_(1B), 5-HT_(1D),and 5-HT_(1E) receptor subtypes. Affinity for these other receptorsubtypes can readily be determined by slight modification of the abovedescribed radioligand receptor binding assays using cells transfectedwith the desired receptor subtype in place of cells transfected with the5-HT_(1F) receptor subtype. The binding affinities of representativecompounds of the present invention were determined by such assays andwere found to be selective for the 5-HT_(1F) receptor; that is theaffinity of the compounds for the 5-HT_(1F) receptor was on the whole,higher than for other receptor subtypes, particular for the 5-HT_(1B)and 5-HT_(1D) receptor subtypes.

Specificity Index

The specificity of compounds of the present invention for 5-HT_(1F)mediated inhibition of neuronal protein extravasation versusvasoconstrictive activity can be expressed with a Specificity Index,which is the ratio of vasoconstriction to efficacy in inhibitingneuronal protein extravasation:${{Specificity}\quad{Index}} = \frac{{Corrected}\quad{Vasoconstriction}\quad{{EC}_{50}(M)}}{{Extravasation}\quad{{ID}_{50}\left( {{m{Mol}}\text{/}{kg}} \right)}}$

The Corrected Vasoconstriction takes into consideration the maximalcontraction relative to KCl for each individual compound, and is definedas the vasoconstriction EC₅₀ value divided by the %_(max) KCl.

For example, sumatriptan has a corrected vasoconstriction EC₅₀ of1.03×10⁻⁸ M (0.66 mM EC₅₀÷64.20%_(max) KCl) and an extravasationinhibition ID₅₀ of 2.6×10−8 mMol/Kg, giving a Specificity Index of 0.40.

Thus the procedure for determining the Specificity Index of any givencompound is as follows:

1. Measure the affinity of the compound for the 5-HT_(1F) receptor usingthe radioligand binding method described above;

2. Once affinity for the 5-HT_(1F) receptor is established, determinewhether the compound is an agonist, partial agonist or antagonist of the5-HT_(1F) receptor by its response in the above described cAMP assay;

3. If the compound is shown to be an agonist or partial agonist with anE_(max) of at least about 50%, measure efficacy of the compound ininhibition of protein extravasation and saphenous vein contraction usingthe above described assays; and

4. Calculate the Specificity Index as shown above.

While compounds with a Specificity Index greater than 1 are useful forthe methods and uses of the present invention, larger values for theSpecificity Index are preferred. A larger Specificity Index indicatesgreater specificity for efficacy in inhibition of neuronal proteinextravasation over vasoconstriction. Thus, preferred compounds have aSpecificity Index of greater than or equal to 10 (at least 10),preferably greater than or equal to 100 (at least 100). More preferredcompounds have a Specificity Index of greater than or equal to 1000 (atleast 1000), and yet more preferred compounds have Specificity Indexesgreater than or equal to 5000 (at least 5000).

Pharmaceutical Compositions

The type of pharmaceutical composition used for the administration ofthe compounds employed in the methods of the present invention may bedictated by the particular compounds selected, the type ofpharmacokinetic profile desired from the route of administration, andthe state of the patient.

Pharmaceutical compositions amenable to oral, sublingual, nasal orinjectable administration are prepared in a manner well known in thepharmaceutical art and comprise at least one active compound. See, e.g.,REMINGTON'S PHARMACEUTICAL SCIENCES, (16^(th) ed. 1980)

In general, a pharmaceutical composition of the present inventionincludes an active ingredient (a compound of formula I) and is usuallymixed with an excipient, diluted by an excipient or enclosed within sucha carrier which can be in the form of a capsule, sachet, paper or othercontainer. When the excipient serves as a diluent, it can be a solid,semi-solid, or liquid material, which acts as a vehicle, carrier ormedium for the active ingredient. Thus, the pharmaceutical compositionscan be in the form of tablets, pills, powders, lozenges, sachets,cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols(as a solid or in a liquid medium), ointments containing for example upto 10% by weight of the active compound, soft and hard gelatin capsules,gels, suppositories, sterile injectable solutions, and sterile packagedpowders.

In preparing a pharmaceutical composition, it may be necessary to millthe active compound to provide the appropriate particle size prior tocombining with the other ingredients. If the active compound issubstantially insoluble, it ordinarily is milled to a particle size ofless than 200 mesh. If the active compound is substantially watersoluble, the particle size is normally adjusted by milling to provide asubstantially uniform distribution in the pharmaceutical composition,e.g., about 40 mesh. In one embodiment of the present invention, theparticle size range is between about 0.1 μm to about 100 μm.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Thepharmaceutical compositions can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl- andpropylhydroxybenzoates; sweetening agents; and flavoring agents. Thecompounds of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

While it is possible to administer a compound employed in the methods ofthis invention directly without any formulation, the compounds areusually administered in the form of pharmaceutical compositionscomprising a pharmaceutically acceptable excipient and at least oneactive ingredient. These formulations can be administered by a varietyof routes including oral, buccal, rectal, intranasal, transdermal,subcutaneous, intravenous, intramuscular, and intranasal. Many of thecompounds employed in the methods of this invention are effective asboth injectable and oral compositions.

In order to administer transdermally, a transdermal delivery device(“patch”) is needed. Such transdermal patches may be used to providecontinuous or discontinuous infusion of a compound of the presentinvention in controlled amounts. The construction and use of transdermalpatches for the delivery of pharmaceutical agents is well known in theart. See, e.g., U.S. Pat. No. 5,023,252. Such patches may be constructedfor continuous, pulsatile, or on demand delivery of pharmaceuticalagents.

Frequently, it will be desirable or necessary to introduce thepharmaceutical composition to the brain, either directly or indirectly.Direct techniques usually involve placement of a drug delivery catheterinto the host's ventricular system to bypass the blood-brain barrier.One such implantable delivery system, used for the transport ofbiological factors to specific anatomical regions of the body, isdescribed in U.S. Pat. No. 5,011,472, which is herein incorporated byreference. The delivery of hydrophilic drugs may be enhanced byintra-arterial infusion of hypertonic solutions, which can transientlyopen the blood-brain barrier.

In one preferred embodiment of the present invention, there is provideda pharmaceutical composition comprising at lest one compound asdescribed above in a pharmaceutical composition adapted for buccaland/or sublingual, or nasal administration. This embodiment providesadministration of the active compound in a manner that avoids gastriccomplications, such as first pass metabolism by the gastric systemand/or through the liver. This administration route may also reduceadsorption times, providing more rapid onset of therapeutic benefit. Thecompounds of the present invention may provide particularly favorablesolubility profiles to facilitate sublingual/buccal pharmaceuticalcompositions. Such pharmaceutical compositions typically requirerelatively high concentrations of active ingredients to deliversufficient amounts of active ingredients to the limited surface area ofthe sublingual/buccal mucosa for the relatively short durations thepharmaceutical composition is in contact with the surface area, to allowthe absorption of the active ingredient. Thus, the very high activity ofthe compounds of the present invention facilitate their suitability forsublingual/buccal pharmaceutical compositions.

A compound of formula I is preferably formulated in a unit dosage form,each dosage containing from about 0.001 to about 100 mg, more usuallyabout 1.0 to about 30 mg, of the active ingredient. The term “unitdosage form” refers to physically discrete units suitable as unitarydosages for human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient as described above.

The compounds of the present invention are generally effective over awide dosage range. For examples, dosages per day normally fall withinthe range of about 0.0001 to about 30 mg/kg of body weight. In thetreatment of adult humans, the range of about 0.1 to about 15 mg/kg/day,in single or divided dose, is especially preferred.

However, it will be understood that the amount of the compound actuallyadministered will be determined by a physician, in the light of therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound or compoundsadministered, the age, weight, and response of the individual patient,and the severity of the patient's symptoms, and therefore the abovedosage ranges are not intended to limit the scope of the invention inany way. In some instances dosage levels below the lower limit of theaforesaid range may be more than adequate, while in other cases stilllarger doses may be employed without causing any harmful side effect,provided that such larger doses are first divided into several smallerdoses for administration throughout the day.

1. A method for activating 5-HT_(1F) receptors in a mammal comprisingadministering to a mammal a compound of formula I:

or a pharmaceutically acceptable acid addition salt thereof, where; X is—C(R^(3C))═ or —N═; R¹ is C₂-C₆ alkyl, substituted C₂-C₆ alkyl, C₃-C₇cycloalkyl, substituted C₃-C₇ cycloalkyl, phenyl, substituted phenyl,heterocycle, or substituted heterocycle; R² is hydrogen, C₁-C₃ n-alkyl,C₃-C₆ cycloalkyl-C₁-C₃ alkyl, or a group of formula II:

R^(3a), R^(3b), and, when X is —C(R^(3c))═, R^(3c), are eachindependently hydrogen, fluoro, or methyl: R⁴ is hydrogen or C₁-C₃alkyl; R⁵ is hydrogen, C₁-C₃ alkyl, or C₃-C₆ cycloalkylcarbonyl; R⁶ ishydrogen or C₁-C₆ alkyl; and n is an integer from 1, 2, 3, 4, 5, and 6inclusively.
 2. The method of claim 1, wherein R¹ is substituted phenyl,further wherein phenyl is substituted with one or more substituentsselected from halo, OCF₃, C₁-C₄ alkyl, and cyano.
 3. The method of claim1, wherein R² is C₁-C₃ n-alkyl.
 4. The method of claim 1, wherein X is—C(R^(3c))═, further wherein R^(3c) is hydrogen.
 5. The method of claim1, wherein R⁴ is hydrogen.
 6. The method of claim 1, wherein R⁵ isselected from hydrogen and C₁-C₃ alkyl.
 7. A method for inhibitingneuronal protein extravasation in a mammal comprising administering thecompound of formula I:

or a pharmaceutically acceptable acid addition salt thereof, where; X is—C(R^(3c))═ or —N═; R¹ is C₂-C₆ alkyl, substituted C₂-C₆ alkyl, C₃-C₇cycloalkyl, substituted C₃-C₇ cycloalkyl, phenyl, substituted phenyl,heterocycle, or substituted heterocycle; R² is hydrogen, C₁-C₃ n-alkyl,C₃-C₆ cycloalkyl-C₁-C₃ alkyl, or a group of formula II

R^(3a), R^(3b), and, when X is —C(R^(3c))═, R^(3c), are eachindependently hydrogen, fluoro, or methyl; R⁴ is hydrogen or C₁-C₃alkyl; R⁵ is hydrogen, C₁-C₃ alkyl, or C₃-C₆ cycloalkylcarbonyl; R⁶ ishydrogen or C₁-C₆ alkyl; and n is an integer from 1, 2, 3, 4, 5, and 6inclusively.
 8. The method of claim 7, wherein R¹ is substituted phenylfurther wherein phenyl is substituted with one or more substituentsselected from halo, OCF₃, C₁-C₄ alkyl, and cyano.
 9. The method of claim7, wherein R² is C₁-C₃ n-alkyl.
 10. The method of claim 7, wherein X is—C(R^(3c))═ further wherein R^(3c) is hydrogen.
 11. The method of claim7, wherein R⁴ is hydrogen.
 12. The method of claim 7, wherein R⁵ isselected from hydrogen and C₁-C₃ alkyl.
 13. A method for treating adisorder associated with dysfunction of the 5-HT_(1F) receptorscomprising administering to a patient in need thereof the compoundaccording to formula I:

or a pharmaceutically acceptable acid addition salt thereof, where; X is—C(R^(3c))═ or —N═; R¹ is C₂-C₆ alkyl, substituted C₂-C₆ alkyl, C₃-C₇cycloalkyl, substituted C₃-C₇ cycloalkyl, phenyl, substituted phenyl,heterocycle, or substituted heterocycle; R² is hydrogen, C₁-C₃ n-alkyl,C₃-C₆ cycloalkyl-C₁-C₃ alkyl, or a group of formula II

R^(3a), R^(3b) and, when X is —C(R^(3c))═, R^(3c), are eachindependently hydrogen, fluoro, or methyl; R⁴ is hydrogen or C₁-C₃alkyl; R⁵ is hydrogen, C₁-C₃ alkyl, or C₃-C₆ cycloalkylcarbonyl; R⁶ ishydrogen or C₁-C₆ alkyl; and n is an integer from 1, 2, 3, 4, 5, and 6inclusively.
 14. The method according to claim 13, wherein the 5-HT_(1F)receptor associated disorder is neuronal protein extravasation.
 15. Themethod of claim 13, wherein the mammal is a human.
 16. The method ofclaim 13, wherein R¹ is substituted phenyl further wherein phenyl issubstituted with one or more substituents selected from halo, OCF₃,C₁-C₄ alkyl, and cyano.
 17. The method of claim 13, wherein R² is C₁-C₃n-alkyl.
 18. The method of claim 13, wherein X is —C(R^(3c))═ furtherwherein R^(3c) is hydrogen.
 19. The method of claim 13, wherein R⁴ ishydrogen.
 20. The method of claim 13, wherein R⁵ is selected fromhydrogen and C₁-C₃ alkyl.